Thiepane compounds

ABSTRACT

Tri- and tetra substituted thiepane compositions having use as immunogens, therapeutics, diagnostics and for other industrial purposes are disclosed. The compositions inhibit proteolytic activity of viral enzymes and are useful for the inhibition of such enzymes as well as in assays for the detection of such enzymes. Embodiments in which antigenic polypeptides are bonded to the compositions are useful in raising antibodies against the thiepane haptens or the polypeptide. Labeled thiepanes of this invention are useful as diagnostic reagents.

This application claims priority from United States Provisional patentapplication Ser. No. 60/007,216 filed Nov. 3, 1995. This application isrelated to U.S. patent application Ser. No. 08/552,429, filed Nov. 3,1995, which was a continuation-in-part of Ser. No. 08 /552,042, filedNov. 2, 1995, which was a continuation-in-part of Ser. No. 08/473, 876,filed Jun. 7, 1995, which was a continuation-in-part of Ser. No.08/470,864, filed Jun. 6, 1995, which was a continuation-in-part of Ser.No. 08/334,471, filed Nov. 4, 1994; each of which is now pending, andall of which are incorporated by reference in their entirety herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

HIV infection and related disease is a major public health problemworldwide. A virally encoded protease (HIV protease) mediates specificprotein cleavage reactions during the natural reproduction of the virus.Accordingly, inhibition of HIV protease is an important therapeutictarget for treatment of HIV infection and related disease.

Assay methods capable of determining the presence, absence or amount ofHIV protease are of practical utility in the search for inhibitors aswell as for diagnosing the presence of HIV.

2. Brief Description of Related Disclosures

Lam, P.; Jadhav, P.; Eyermann, C.; Hodge, C.; De Lucca, G.; and Rodgers,J.; WO 94/19329, Sep. 1, 1994, discloses substituted cyclic carbonylsand derivatives thereof useful as retroviral protease inhibitors.

Billich, A.; Billich, S.; and Rosenwirth, B; Antiviral Chem. & Chemoth.,1991, 2(2), 65-73, discloses assays for HIV protease.

Matayoshi, E. D.; Wang, G. T.; Krafft, G. A.; and Erickson, J. W.;Science, 1990, 247, 954-958; and Wang, G. T.; Huffker, J. A.; Matayoshi,E.; and Krafft, G. A.; Tetrahedron Lett., 1990, 165, 6493-6496; disclosea fluorometric assay method for measurement of HIV-protease (HIV-PR)activity utilizing a synthetic peptide substrate for HIV-PR.

Wong, Y.; Burcham, D.; Saxton, P.; Erickson-Viitanen, S.; Grubb, M.;Quon, C.; and Huang, S.-M.; Biopharm. & Drug Disp., 1994, 15, 535-544,discloses pharmacokinetic evaluation of cyclic urea HIV proteaseinhibitors in rats and dogs.

Inhibition of HIV protease is an object of the invention. Inhibitors ofHIV protease are useful to limit the establishment and progression ofinfection by HIV as well as in assays for HIV protease, both of whichare further objects of the invention. Preparation of compositionscapable of inhibiting HIV protease is also an object of the invention.

Thus, it is an object of this invention to provide HIV proteaseinhibitors having improved antiviral and pharmacokinetic properties,including enhanced activity against development of HIV resistance,improved oral bioavailability, greater potency and extended effectivehalf-life in vivo. It is another object herein to provide compoundsuseful in diagnostic assays for HIV, for use in the preparation ofpolymers and for use as surfactants, and in other industrial utilitiesthat will be readily apparent to the artisan.

SUMMARY OF THE INVENTION

Compositions of the invention comprise compounds of the formula:##STR1## wherein: Y is independently --O--, --S--, --SO--, --SO₂ --,--N(R₁)--, --N(R₁)--SO₂ --, --N(R₁)--CO--, or --O--SO₂ --;

E and U are independently H, or --(CR₁ R₁)_(m1) --W₁, with the provisothat at least one of E and U is --(CR₁ R₁)_(m1) --^(W) ₁ ;

G and T are independently --(CR₁ R₁)_(m1) --W₁, or --(CR₁ R₁)_(m1)--C(R₁)(W₁)(W₂), with the provisos that:

when E is --(CR₁ R₁)_(m1) --W₁, then G is --(CR₁ R₁)_(m1) --W₁ ;

when U is --(CR₁ R₁)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁ ; and Gand T may be the same or different;

J and L are independently H, N₃, --OR₂, --N(R₂)(R₂), or --N(R₂)(R₃),wherein R₂ is H, or PRT, with the proviso that at least one of J and Lis --OR₂, or J and L are taken together to form an epoxide or a cyclicprotecting group;

W₁ is W₂ or W₃ ;

W₂ is carbocycle or heterocycle, with the proviso that each W₂ isindependently substituted with 0 to 3 R₅ groups;

W₃ is alkyl, alkenyl, or alkynyl, with the proviso that each W₃ isindependently substituted with 0 to 3 R₆ groups;

R₁ is R₃ or R₆ ;

R₃ is H or R₄ ;

R₄ is alkyl;

R₅ is R₆, or R₇, with the proviso that each R₇ is independentlysubstituted with 0 to 3 R₆ groups;

R₆ is --O-(antigenic polypeptide), --N(R₃)-(antigenic polypeptide),--C(O)O-(antigenic polypeptide), --C(O)N(R₃)-(antigenic polypeptide),--S--(antigenic polypeptide), --S--S-(antigenic polypeptide),--O-(label), --N(R₃)-(label), --C(O)O-(label), --C(O)N(R₃)-(label),--S-(label), --S--S-(label), F, Cl, Br, I, --CN, N₃, --NO₂, --OR₃,--OPRT, --O--C(O)R₄, ═O, --N(R₃)(R₃), --N(R₃)(PRT), --N(PRT)₂,--N(R₃)--C(O)R₄, ═N(R₃), ═N(PRT), --N(OR₃)(R₃), --N(OPRT)(R₃),--N(OR₃)(PRT), --N(OPRT)(R₃), --N(N(R₃)(R₃))(R₃), --N(N(PRT)(R₃))(R₃),--N(N(R₃)(R₃))(PRT), --N(N(PRT)(PRT))(R₃), --N(N(PRT)(R₃))(PRT),--N(N(PRT)(PRT))(PRT), --N(R₃)--C(N(R₃))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)₂), --N(R₃)--C(N(PRT))(N(R₃)₂),--N(R₃)--C(N(R₃))(N(R₃)(PRT)), --N(PRT)--C(N(PRT))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)(PRT)), --N(R₃)--C(N(PRT))(N(R₃)(PRT)),--N(R₃)--C(N(R₃))(N(PRT)₂), --N(PRT)--C(N(PRT))(N(R₃)(PRT)),--N(PRT)--C(N(R₃))(N(PRT)₂), --N(R₃)--C(N(PRT))(N(PRT)₂),--N(PRT)--C(N(PRT))(N(PRT)₂), --C(NR₃)(N(R₃)₂), --C(N(R₃))(N(R₃)(PRT)),--C(NPRT)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂),--C(N(PRT))(N(PRT)₂), --SR₃, --S(PRT), ═S, --S(O)--R₃, --S(O)--OR₃,--S(O)--OPRT, --O--S(O)--R₃, --S(O)₂ --R₃, --S(O)₂ --OR₃, --S(O)₂--OPRT, --O--S(O)₂ --R₃, --C(O)OR₃, --C(O)OPRT, --C(O)N(R₃)₂,--C(O)N(R₃)(PRT), --C(O)N(PRT)₂, --C(S)N(R₃)₂, --C(S)N(R₃)(PRT),--C(S)N(PRT)₂, --N(R₃)--S(O)₂ --R₃, --N(PRT)--S(O)₂ --R₃, --S(O)₂--N(R₃)--R₃, --S(O)₂ --N(PRT)--R₃, carbocycle, or heterocycle;

R₇ is alkyl, alkenyl, or alkynyl;

m1 is an integer from 0 to 3; and with the proviso that the compound,taken as a whole, contains 0 to 16 R₆ groups, and that each E, G, T, andU, taken individually, contain 0 to 8 R₆ groups.

The invention is also directed to methods of detecting the presence oramount of HIV protease comprising contacting a test sample with acomposition of the invention comprising a detectable label.

The invention is also directed to methods of inhibiting the activity ofHIV protease comprising contacting the protease with an inhibitoryeffective amount of a composition of the invention.

DETAILED DESCRIPTION Compositions of the Invention

Compositions of the invention comprise compounds of the formulas:##STR2##

The E, G, T and U groups may be the same or different. Y isindependently --O--, --S--, --SO--, --SO₂ --, --N(R₁)--, --N(R₁)--SO₂--, --N(R₁)--CO--, or --O--SO₂ --.

Typically the compositions of the invention comprise compounds of theformula: ##STR3##

More typically the compositions of the invention comprise compounds ofthe formula: ##STR4##

                  TABLE 1                                                         ______________________________________                                        Intended Stereochemistries of Formulas I, II and III                          ______________________________________                                        αE, αG, αJ, αL, αT, αU                                       αE, αG, αJ, αL, αT,                             βU                                                    αE, αG, αJ, αL, βT, αU                                        αE, αG, αJ, αL, βT,                              βU                                                    αE, αG, αJ, βL, αT, αU                                        αE, αG, αJ, βL, αT,                              βU                                                    αE, αG, αJ, βL, βT, αU                                         αE, αG, αJ, βL, βT,                               βU                                                    αE, αG, βJ, αL, αT, αU                                        αE, αG, βJ, αL, αT,                              βU                                                    αE, αG, βJ, αL, βT, αU                                         αE, αG, βJ, αL, βT,                               βU                                                    αE, αG, βJ, βL, αT, αU                                         αE, αG, βJ, βL, αT,                               βU                                                    αE, αG, βJ, βL, βT, αU                                          αE, αG, βJ, βL, βT,                                βU                                                    αE, βG, αJ, αL, αT, αU                                        αE, βG, αJ, αL, αT,                              βU                                                    αE, βG, αJ, αL, βT, αU                                         αE, βG, αJ, αL, βT,                               βU                                                    αE, βG, αJ, βL, αT, αU                                         αE, βG, αJ, βL, αT,                               βU                                                    αE, βG, αJ, βL, βT, αU                                          αE, βG, αJ, βL, βT,                                βU                                                    αE, βG, βJ, αL, αT, αU                                         αE, βG, βJ, αL, αT,                               βU                                                    αE, βG, βJ, αL, βT, αU                                          αE, βG, βJ, αL, βT,                                βU                                                    αE, βG, βJ, βL, αT, αU                                          αE, βG, βJ, βL, αT,                                βU                                                    αE, βG, βJ, βL, βT, αU                                           αE, βG, βJ, βL, βT, βU      βE, αG, αJ, αL, αT, αU                                        βE, αG, αJ, αL, αT,                              βU                                                    βE, αG, αJ, αL, βT, αU                                         βE, αG, αJ, αL, βT,                               βU                                                    βE, αG, αJ, βL, αT, αU                                         βE, αG, αJ, βL, αT,                               βU                                                    βE, αG, αJ, βL, βT, αU                                          βE, αG, αJ, βL, βT,                                βU                                                    βE, αG, βJ, αL, αT, αU                                         βE, αG, βJ, αL, αT,                               βU                                                    βE, αG, βJ, αL, βT, αU                                          βE, αG, βJ, αL, βT,                                βU                                                    βE, αG, βJ, βL, αT, αU                                          βE, αG, βJ, βL, αT,                                βU                                                    βE, αG, βJ, βL, βT, αU                                           βE, αG, βJ, βL, βT, βU      βE, βG, αJ, αL, αT, αU                                         βE, βG, αJ, αL, αT,                               βU                                                    βE, βG, αJ, αL, βT, αU                                          βE, βG, αJ, αL, βT,                                βU                                                    βE, βG, αJ, βL, αT, αU                                          βE, βG, αJ, βL, αT,                                βU                                                    βE, βG, αJ, βL, βT, αU                                           βE, βG, αJ, βL, βT, βU      βE, βG, βJ, αL, αT, αU                                          βE, βG, βJ, αL, αT,                                βU                                                    βE, βG, βJ, αL, βT, αU                                           βE, βG, βJ, αL, βT, βU      βE, βG, βJ, βL, αT, αU                                           βE, βG, βJ, βL, αT, βU      βE, βG, βJ, βL, βT, αU                                            βE, βG, βJ, βL, βT,               ______________________________________                                                           βU                                                     E, G, T, and U                                                            

In all embodiments, E and U are independently H, or --(CR₁ R₁)_(m1)--W₁, provided that at least one of E and U is --(CR₁ R₁)_(m1) --W₁.Typically E and U are independently groups of the formula --(CR₁R₁)_(m1) --W₂, more typically, --(CR₃ R₃)_(m1) --W₂. Preferably, E and Uare not H.

G and T are independently --(CR₁ R₁)_(m1) --W₁, or --(CR₁ R₁)_(m1)--C(R₁)(W₁)(W₂), provided that when E is --(CR₁ R₁) _(m1) --W₁, G is--(CR₁ R₁)_(m1) --W₁, and when U is --(CR₁ R₁)_(m1) --W₁, T is --(CR₁R₁)_(m1) --W₁. Typically, G and T are independently groups of theformula --(CR₁ R₁)_(m1) --W₂, more typically, --(CR₃ R₃)_(m1) --W₂.

In another embodiment, E, G, T and U are all --(CR₁ R₁)_(m1) --W₁.Typically, E, G, T and U are --(CR₃ R₃)_(m1) --W₁. More typically, E, G,T and U are --(CR₁ R₁)_(m1) --W₂. Still more typically, E, G, T and Uare --(CR₃ R₃)_(m1) --W₂.

In another embodiment one of E and U is H and the other is --(CR₁R₁)_(m1) --W₁ ; and T and G are --(CR₁ R₁) _(m1) --W₁. Typically, one ofE and U is H and the other is --(CR₃ R₃)_(m1) --W₁ ; and T and G are--(CR₃ R₃)_(m1) --W₁. More typically, one of E and U is H and the otheris --(CR₁ R₁)_(m1) --W₂ ; and T and G are --(CR₁ R₁)_(m1) --W₂. Stillmore typically, one of E and U is H and the other is --(CR₃ R₃)_(m1)--W₂ ; and T and G are --(CR₃ R₃)_(m1) --W₂.

In another embodiment one of E and U is H and the other is --(CR₁R₁)_(m1) --W₁, provided that when E is H, then G is --(CR₁ R₁)_(m1)--C(R₁)(W₁)(W₂), when E is --(CR₁ R₁)_(m1) --W₁, then G is --(CR₁R₁)_(m1) --W₁, when U is H, then T is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂),and when U is --(CR₁ R₁)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁.Typically, one of E and U is H and the other is --(CR₃ R₃)_(m1) --W₁,provided that when E is H, then G is --(CR₁ R₁)_(m1) --C (R₁)(W₁)(W₂),when E is --(CR₃ R₃)_(m1) --W₁, then G is --(CR₁ R₁)_(m1) --W₁, when Uis H, then T is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), and when U is --(CR₃R₃)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁. More typically, one of Eand U is H and the other is --(CR₁ R₁)_(m1) --W₂, provided that when Eis H, then G is --(CR₁ R₁)_(m1) --C (R₁)(W₁)(W₂), when E is --(CR₁R₁)_(m1) --W₂, then G is --(CR₁ R₁)_(m1) --W₁, when U is H, then T is--(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), and when U is --(CR₁ R₁)_(m1) --W₂,then T is --(CR₁ R₁)_(m1) --W₁. Still more typically one of E and U is Hand the other is --(CR₃ R₃)_(m1) --W₂, provided that when E is H, then Gis --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), when E is --(CR₃ R₃)_(m1) --W₂, thenG is --(CR₁ R₁)_(m1) --W₁, when U is H, then T is --(CR₁ R₁)_(m1)--C(R₁)(W₁)(W₂), and when U is --(CR₃ R₃)_(m1) --W₂, then T is --(CR₁R₁)_(m1) --W₁.

In another embodiment, E, G, T and U are independently --CR₃ R₃ --W₂wherein R₃ is H or a 1 to 3 carbon alkyl group and W₂ is a monocycliccarbocycle (3 to 6 carbon atoms) or monocyclic heterocycle (3 to 6 ringmembers, 2 to 5 carbon atoms, and 1 to 2 heteroatoms selected from O, N,and S) provided that W₂ is substituted with 0 to 1 --OH, --OMe, --NH₂,--N(H)(Me), --N(H)(Et), --N(H)(i--Pr), --N(H)(n--Pr), --N(Me)₂, --NO₂,or --CN. Typically, in this embodiment W₂ is phenyl, pyridyl,tetrahydrothiophene, sulfur oxidized (sulfoxide or sulfone)tetrahydrothiophene, or thiazole.

In another embodiment, E, G, T and U are independently --CR₃ R₃ --W₂wherein W₂ is phenyl or thiazole provided that each W₂ is independentlysubstituted with 0, 1 or 2 R₅ groups as described above.

In another embodiment, E, G, T and U are independently --CHR₃ --W₂wherein W₂ is phenyl or thiazole provided that each W₂ is independentlysubstituted with 0 to 1 R₅ groups as described above.

In another embodiment, E, G, T and U are independently --CHR₃ --W₂wherein W₂ is phenyl or thiazole provided that each W₂ is independentlysubstituted with 0 to 1 R₃ groups as described above.

In another embodiment, E, G, T and U are benzyl.

Another embodiment is directed to compositions of the formula: ##STR5##

E, G, J, L, T, and U are as described above.

E, G, T, and U, when taken individually, are substituted with no morethan 8 R₆ groups, typically, no more than 3 R₄ or R₇ and 6 R₆ groups.More typically, each is substituted with 1 or 2 R₄ or R₇ groups of 1 or3, or 2 or 3 carbon atoms, respectively, and 0 to 4 R₆ groups selectedfrom --OR₃, --SR₃, --N(R₃)(R₃), F, CN, --NO₂, and heterocycle. Stillmore typically, each is substituted with 0 or 1 R₄ of 1 to 3 carbonatoms and 0 or 1 R₆ groups selected from --OH, --OMe, --OEt, --NH₂,--N(H)(Me) F, CN, --NO₂, 1-aziridyl, and 1-azetidyl.

Additional exemplary E, G, T, and U groups are described below in Table12.

Additional exemplary compositions of the invention are described inTable 14.

R₁ is R₃ or R₆.

R₃ is H or R₄.

R₄ is alkyl. Typically, R₄ is an alkyl of 1 to 6 carbon atoms such asmethyl (Me, --CH₃), ethyl (Et, --CH₂ CH₃), 1-propyl (n-Pr, n-propyl,--CH₂ CH₂ CH₃), 2-propyl (i-Pr, i-propyl, --CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, --CH₂ CH₂ CH₂ CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, --CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, --CH(CH₃)CH₂ CH₃), 2-methyl-2-propyl(t-Bu, t-butyl, --C(CH₃)₃), 1-pentyl (n-pentyl, --CH₂ CH₂ CH₂ CH₂ CH₃),2-pentyl (--CH(CH₃)CH₂ CH₂ CH₃), 3-pentyl (--CH(CH₂ CH₃)₂),2-methyl-2-butyl (--C(CH₃)₂ CH₂ CH₃), 3-methyl-2-butyl(--CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (--CH₂ CH₂ CH(CH₃)₂),2-methyl-1-butyl (--CH₂ CH(CH₃)CH₂ CH₃), 1-hexyl (--CH₂ CH₂ CH₂ CH₂ CH₂CH₃), 2-hexyl (--CH(CH₃)CH₂ CH₂ CH₂ CH₃), 3-hexyl (--CH(CH₂ CH₃)(CH₂ CH₂CH₃)), 2-methyl-2-pentyl (--C(CH₃)₂ CH₂ CH₂ CH₃), 3-methyl-2-pentyl(--CH(CH₃)CH(CH₃)CH₂ CH₃), 4-methyl-2-pentyl (--CH(CH₃)CH₂ CH(CH₃)₂),3-methyl-3-pentyl (--C(CH₃)(CH₂ CH₃)₂), 2-methyl-3-pentyl (--CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (--C(CH₃)₂ CH(CH₃)₂),3,3-dimethyl-2-butyl (--CH(CH₃)C(CH₃)₃), or the like. More typically, R₄is an alkyl of 1, 2, 3 or 4 carbon atoms. Still more typically, R₄ is analkyl of 1, 2 or 3 carbon atoms selected from methyl, ethyl, n-propyl,and i-propyl.

R₅ is R₆ or R₇, provided that each R₇ is independently substituted with0 to 3 R₆ atoms or groups. R₆ and R₇ are as defined below. Typically, R₅is R₆, unsubstituted R₇ or mono-, di- and trihaloalkyls of 1 to 6 carbonatoms, more typically, mono- di-, and trifluoro-n-alkyls of 1, 2 or 3carbon atoms, still more typically monofluoromethyl, difluoromethyl, ortrifluoromethyl.

R₆ is --O-(antigenic polypeptide), --N(R₃)-(antigenic polypeptide),--C(O)O-(antigenic polypeptide), --C(O)N(R₃)-(antigenic polypeptide),--S--(antigenic polypeptide), --S--S-(antigenic polypeptide),--O-(label), --N(R₃)-(label), --C(O)O-(label), --C(O)N(R₃)-(label),--S-(label), --S--S-(label), F, Cl, Br, I, --CN, N₃, --NO₂, --OR₃,--OPRT, --O--C(O)R₄, ═O, --N(R₃)(R₃), --N(R₃)(PRT), --N(PRT)₂,--N(R₃)--C(O)R₄, ═N(R₃), ═N(PRT), --N(OR₃)(R₃), --N(OPRT)(R₃),--N(OR₃)(PRT), --N(OPRT)(R₃), --N(N(R₃)(R₃))(R₃), --N(N(PRT)(R₃))(R₃),--N(N(R₃)(R₃))(PRT), --N(N(PRT)(PRT))(R₃), --N(N(PRT)(R₃))(PRT),--N(N(PRT)(PRT))(PRT), --N(R₃)--C(N(R₃))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)₂), --N(R₃)--C(N(PRT))(N(R₃)₂),--N(R₃)--C(N(R₃))(N(R₃)(PRT)), --N(PRT)--C(N(PRT))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)(PRT)), --N(R₃)--C(N(PRT))(N(R₃)(PRT)),--N(R₃)--C(N(R₃))(N(PRT)₂), --N(PRT)--C(N(PRT))(N(R₃)(PRT)),--N(PRT)--C(N(R₃))(N(PRT)₂), --N(R₃)--C(N(PRT))(N(PRT)₂),--N(PRT)--C(N(PRT))(N(PRT)₂), --C(NR₃)(N(R₃)₂), --C(N(R₃))(N(R₃)(PRT)),--C(NPRT)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂),--C(N(PRT))(N(PRT)₂), --SR₃, --S(PRT), ═S, --S(O)--R₃, --S(O)--OR₃,--S(O)--OPRT, --O--S(O)--R₃, --S(O)₂ --R₃, --S(O)₂ --OR₃, --S(O)₂--OPRT, --O--S(O)₂ --R₃, --C(O)OR₃, --C(O)OPRT, --C(O)N(R₃)₂,--C(O)N(R₃)(PRT), --C(O)N(PRT)2, --C(S)N(R₃)₂, --C(S)N(R₃)(PRT),--C(S)N(PRT)₂, --N(R₃)--S(O)₂ --R₃, --N(PRT)--S(O)₂ --R₃, --S(O)₂--N(R₃)--R₃, --S(O)₂ --N(PRT)--R₃, carbocycle, or hetercycle. OrdinarilyR₆ is --O--(antigenic polypeptide), --N(R₃)-(antigenic polypeptide),--C(O)O--(antigenic polypeptide), --C(O)N(R₃)-(antigenic polypeptide),F, Cl, Br, I, --CN, N₃, --NO₂, --OR₃, --N(R₃)(R₃), --SR₃, --O--C(O)R₄,--N(R₃)--C(O)R₄, --C(O)N(R₃)(PRT), --C(O)N(PRT)₂, --C(O)N(R₃)₂,--C(O)OR₃, --OPRT, --N(PRT)₂, --C(NR₃)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)),--C(N(R₃))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂), --C(N(PRT))(N(PRT)₂),--N(R₃)(PRT), --S(PRT), carbocycle or heterocycle. Typically, R₆ groupsare selected from --OR₃, --SR₃, --N(R₃)(R₃), F, CN, --NO₂, andheterocycle. More typically, R₆ groups are selected from --OH, --OMe,--OEt, --O--i--Pr, --NH₂, --N(H)(Me), F, CN, --NO₂, 1-aziridyl, and1-azetidyl.

When R₆ is carbocycle or heterocycle, it is typically a monocycle having3 or 4 ring atoms, more typically, it is a heterocycle having 2 to 3carbon atoms and 1 heteroatom selected from O, S, and N, still moretypically, it is aziridyl, or azetidyl, more typically yet, it is1-aziridyl, or 1-azetidyl. Other heterocycles or carbocycles suitablefor R₆, and their substitution sites, are described below under W₂.

W₁ is W₂ or W₃.

W₂ is carbocycle or heterocycle. Carbocycles and heterocycles within thecontext of W₂ are stable chemical structures. Such structures areisolatable in measurable yield, with measurable purity, from reactionmixtures at temperatures from -78° C. to 200° C. Each W₂ isindependently substituted with 0 to 3 R₆ groups. Typically, W₂ is asaturated, unsaturated or aromatic ring comprising a mono- or bicycliccarbocycle or heterocycle. More typically, W₂ has 3 to 10 ring atoms,still more typically, 3 to 7 ring atoms.

Typically, W₂ is a carbocyclic or heterocyclic monocycle with 3 to 6ring atoms. The carbocycles or heterocycles are typically saturated ifthey have 3 ring atoms, saturated or monounsaturated if they have 4 ringatoms, saturated, or mono- or diunsaturated if they have 5 ring atoms,and saturated, mono- or diunsaturated, or aromatic if they have 6 ormore ring atoms.

When W₂ is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7to 10 carbon atom bicycle. More typically, W₂ monocyclic carbocycleshave 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Moretypically, W₂ bicyclic carbocycles have 7 to 10 ring atoms arranged as abicyclo 4,5!, 5,5!, 5,6! or 6,6! system, still more typically, 9 or 10ring atoms arranged as a bicyclo 5,6! or 6,6! system. Examples includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl.

When W₂ is a heterocycle, it is typically a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 3 heteroatoms selected from N, O, P, and S). More typically, W₂heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and1 to 2 heteroatoms selected from N, O, and S), still more typically, 5or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selectedfrom N and S). More typically, W₂ heterocyclic bicycles have 7 to 10ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N,O, and S) arranged as a bicyclo 4,5!, 5,5!, 5,6!, or 6,6! system, stillmore typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo 5,6! or 6,6!system.

Heterocycles include by way of example and not limitation thosedescribed in Paquette, Leo A.; "Principles of Modern HeterocyclicChemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series ofMonographs" (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960,82, 5566; each of which is incorporated herein by reference.

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H, 6H-1,5 2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

Typically W₂ heterocycles are selected from pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, orpyrrolyl.

In general the W₂ heterocycle is bonded to --(CR₁ R₁)_(m1) -- through aring carbon or heteroatom and, where the heterocycle is polycyclic,through a nonbridging hetero or carbon atom. Aromatic heterocycles arebonded typically through a nonbridging carbon or heteroatom. Usually,the W₂ heterocycle is bonded through a carbon atom. For example, W₂ isbonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, positon 2, 3,5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, the heterocycle of W₂ is 2-pyridyl,3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

Ordinary and typical W₂ 's are selected from those shown in Table 2.More typically, W₂ is phenyl, thiazole, tetrahydrothiophene, and sulfuroxidized tetrahydrothiophene structures.

                  TABLE 2                                                         ______________________________________                                        Ordinary W.sub.2 s                                                             ##STR6##                                                                      ##STR7##                                                                      ##STR8##                                                                      ##STR9##                                                                      ##STR10##                                                                    Typical W.sub.2 s                                                              ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                    ______________________________________                                    

R₇ is alkyl, alkenyl, or alkynyl. Typically, R₇ is a group of 1 to 8carbon atoms. When R₇ is alkyl it is typically selected from thosedescribed above with respect to R₄ and the corresponding 7 and 8 carbonhomologs. When R₇ is alkenyl it is a group of 2 to 8 carbons, typicallyethenyl (--CH═CH₂), 1-prop-1-enyl (--CH═CHCH₃), 1-prop-2-enyl (--CH₂CH═CH₂), 2-prop-1-enyl (--C(═CH₂)(CH₃)), 1-but-1-enyl (--CH═CHCH₂ CH₃),1-but-2-enyl (--CH₂ CH=CHCH₃), 1-but-3-enyl (--CH₂ CH₂ CH═CH₂),2-methyl-1-prop-1-enyl (--CH═C(CH₃)₂), 2-methyl-1-prop-2-enyl (--CH₂C(═CH₂)(CH₃)), 2-but-1-enyl (--C(═CH₂)CH₂ CH₃), 2-but-2-enyl(--C(CH₃)═CHCH₃), 2-but-3-enyl (--CH(CH₃)CH═CH₂), 1-pent-1-enyl(--C═CHCH₂ CH₂ CH₃), 1-pent-2-enyl (--CHCH═CHCH₂ CH₃), 1-pent-3-enyl(--CHCH₂ CH═CHCH₃), 1-pent-4enyl (--CHCH₂ CH₂ CH═CH₂), 2-pent-1-enyl(--C(═CH₂)CH₂ CH₂ CH₃), 2-pent-2-enyl (--C(CH₃)═CH₂ CH₂ CH₃),2-pent-3-enyl (--CH(CH₃)CH═CHCH₃), 2-pent-4-enyl (--CH(CH₃)CH₂ CH═CH₂),3-methyl-1-but-2-enyl (-CH₂ CH═C(CH₃)2), or the like. More typically, R₇alkenyl groups are of 2 to 6 carbon atoms, still more typically, 2, 3 or4 carbon atoms. When R₇ is alkynyl it is a group of 2 to 8 carbon atoms,typically ethynyl (--CCH), 1-prop-1-ynyl (--CCCH₃), 1-prop-2-ynyl (--CH₂CCH), 1-but-1-ynyl (--CCCH₂ CH₃), 1-but-2-ynyl (--CH₂ CCCH₃),1-but-3-ynyl (--CH₂ CH₂ CCH), 2-but-3-ynyl (CH(CH₃)CCH), 1-pent-1-ynyl(--CCCH₂ CH₂ CH₃), 1-pent-2-ynyl (--CH₂ CCCH₂ CH₃), 1-pent-3-ynyl (--CH₂CH₂ CCCH₃), 1-pent-4-ynyl (--CH₂ CH₂ CH₂ CCH), or the like. Moretypically, R₇ alkynyl groups are of 2 to 6 carbon atoms. Still moretypically, 2, 3 or 4 carbon atoms.

W₃ is alkyl, alkenyl, or alkynyl provided that each W₃ is independentlysubstituted with 0 to 2 R₆ groups. Typically, W₃ is an alkyl of 1 to 8carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8carbon atoms. Such groups are described above with respect to R₇. Moretypically, W₃ is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6carbon atoms, or alkynyl of 2 to 6 carbon atoms. Still more typically,W₃ is an alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms,or alkynyl of 2 to 3 carbon atoms.

Each m1 is an integer from 0 to 3, typically 0 to 2, and more typically0 or 1. When E, G, T, or U, contains a W₂ heterocycle group and m1 is 0,then W₂ is typically bonded through a carbon atom of W₂ as describedabove.

In one embodiment of the invention, Y is --O--, and both G and T arehydroxy protecting groups as described below. In another embodiment ofthe invention, Y is --O--, and one or both of G and T are not a hydroxyprotecting group. For example, in the latter case when Y is --O-- andone or both of G and T are benzyl, then one or both of the benzyls issubstituted in such a way as to render it not useful as a hydroxyprotecting group, e.g. not useful in the method described in Greene(cited below). Such substitutions include by way of example and notlimitation, incorporation of a protonatable group in the meta positionof the benzene ring of a benzyl group to render the group non-removableby conventional debenzylation methods or to render the group cleavable,but only under conditions that do not result in cleavage of conventionalbenzyl protecting groups. Such groups include R₆ groups containingsulfur, nitrogen or oxygen. Typical benzyls of this type include metaamino, sulfhydryl, and hydroxyl substituted benzyls. G and T optionallyare selected to be stable in acid or base deprotecting conditions usedheretofore to remove OH protecting groups.

I and L

J and L are independently H, N₃, --OR₂, --N(R₂)(R₂), or --N(R₂)(R₃)provided that at least one of J and L is --OR₂. Alternatively, J and Lare taken together to form an epoxide, or a cyclic protecting group.

Typically, one of J and L is --OH. In this embodiment, the other of Jand L is typically, --OH, --NH₂, --N(R₃)(H) or H. More typically, theother of J and L is --OH. In another typical embodiment, one of J and Lis --OR₈ and the other is H, --OR₂, --N(R₂)(R₂), or --N(R₂)(R₃). In thisembodiment, R₈ is --(CR₃ R₃)_(m2) --C (O)(Rg), --(CR₃ R₃)_(m2)-P(O)(R₉)(R₉), or --(CR₃ R₃)_(m2) -S(O)₂ (R₉), Rg is W₁, --OW₁,--N(R₃)(W₁), --N(W₁)(W₁), or --SW₁, and _(m2) is an integer from 0 to 2,typically 0 to 1. Other ordinary and typical embodiments of J and L aredepicted in Table 3.

In each of the embodiments of J and L, R₃ is typically H or an alkylgroup of 1, 2 or 3 carbon atoms as described above with respect to R₄.

                  TABLE 3                                                         ______________________________________                                        Ordinary Epoxide and Cyclic Protecting Groups of J and L                       ##STR19##                                                                     ##STR20##                                                                     ##STR21##                                                                    Typical Epoxide and Cyclic Protecting Groups of J and L                        ##STR22##                                                                     ##STR23##                                                                    ______________________________________                                    

R₂ is H. or a cyclic protecting group. When J or L is --OR₂,--N(R₂)(R₂), or --N(R₂)(R₃), R₂ is H, or PRT.

PRT

A very large number of protecting groups (PRT) and cyclic protectinggroups and corresponding cleavage reactions are described in "ProtectiveGroups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons,Inc., New York, 1991, ISBN 0-471-62301-6)(Greene) and will not bedetailed here. In the context of the present invention, these protectinggroups are groups that can be removed from the molecule of the inventionwithout irreversibly changing the covalent bond structure oroxidation/reduction state of the remainder of the molecule. For example,PRT of a --OPRT or --N(R₃)(PRT) group can be removed to form a --OH or--N(R₃)(H) group, respectively, without affecting other covalent bondsin the molecule. At times, when desired, more than one PRT group can beremoved at a time, or they can be removed sequentially. In compounds ofthe invention containing more than one PRT, the PRT are the same ordifferent.

Determination of whether a group is a protecting group is made in theconventional manner, illustrated by the work of Kocienski, Section 1.1,page 2, and Greene Chapter 1, pages 1-9, both cited herein. Inparticular, a group is a protecting group if when, based on mole ratio,90% of that protecting group has been removed by a deprotectionreaction, no more than 50%, preferably 25%, more preferably 10%, of thedeprotected product molecules of the invention have undergone changes totheir covalent bond structure or oxidation/reduction state other thanthose occasioned by the removal of the protecting group. When multipleprotecting groups of the same type are present in the molecule, the moleratios are determined when all of the groups of that type are removed.When multiple protecting groups of different types are present in themolecule, each type of protecting group is treated (and the mole ratiosare determined) independently or together with others depending onwhether the deprotection reaction conditions pertinent to one type arealso pertinent to the other types present. In one embodiment of theinvention, a group is a protecting group if when, based on mole ratiodetermined by conventional techniques, 90% of that protecting group hasbeen removed by a conventional deprotection reaction, no more than 50%,preferably 25%, more preferably 10%, of the deprotected productmolecules of the invention have undergone irreversible changes to theircovalent bond structure or oxidation/reduction state other than thoseoccasioned by the removal of the protecting group. Irreversible changesrequire chemical reactions (beyond those resulting from aqueoushydrolysis, acid/base neutralization or conventional separation,isolation or purification) to restore the covalent bond structure oroxidation/reduction state of the deprotected molecule of the invention.

Protecting groups are also described in detail together with generalconcepts and specific strategies for their use in Kocienski, Philip J.;"Protecting Groups" (Georg Thieme Verlag Stuttgart, New York,1994)(Philip), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184, Chapter 6, Amino Protecting Groups, pages 185-243, Chapter 7,Epilogue, pages 244-252, and Index, pages 253-260, are incorporated withspecificity in the context of their contents. More particularly,Sections 2.3 Silyl Ethers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers(Acetals), 2.6 Reviews (hydroxy and thiol protecting groups), 3.2Acetals, 3.3 Silylene Derivatives, 3.41,1,3,3-Tetraisopropyldisiloxanylidene Derivatives, 3.5 Reviews (diolprotecting groups), 4.2 Esters, 4.3 2,6,7-Trioxabicyclo 2.2.2!octanesOBO! and Other Ortho Esters, 4.4 Oxazolines, 4.5 Reviews (carboxylprotecting groups), 5.2 O,O-Acetals, 5.3 S,S-Acetals, 5.4 O,S-Acetals,5.5 Reviews (carbonyl protecting groups), 6.2 N-Acyl Derivatives, 6.3N-Sulfonyl Derivatives, 6.4 N-Sulfenyl Derivatives, 6.5 N-AlkylDerivatives, 6.6 N-Silyl Derivatives, 6.7 Imine Derivatives, and 6.8Reviews (amino protecting groups), are each incorporated withspecificity where protection/deprotection of the requisitefunctionalities is discussed. Further still, the tables "Index to thePrincipal Protecting Groups" appearing on the inside front cover andfacing page, "Abbreviations" at page xiv, and "reagents and Solvents" atpage xv are each incorporated in their entirety herein at this location.

Typical hydroxy protecting groups are described in Greene at pages14-118 and include Ethers (Methyl); Substituted Methyl Ethers(Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl,(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,1-Methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-Methoxytetrahydrothiopyranyl, 4-MethoxytetrahydropthiopyranylS,S-Dioxido, 1- (2-Chloro-4-methyl)phenyl!-4-methoxypiperidin-4-yl, 35,1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl);Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl,1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl,1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl,2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl, ,p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); SubstitutedBenzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,Diphenylmethyl, p, p'-Dinitrobenzhydryl, 5-Dibenzosuberyl,Triphenylmethyl, α-Naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl,4,4', 4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl,9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers(Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate,4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,2,4,6-Trimethylbenzoate (Mesitoate); Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With AssistedCleavage (2-Iodobenzoate, 4-Azidobutyrate, 4Niotro-4-methylpentanoate,o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters(2,6-Dichloro-4-methylphenoxyacetate,2,6-Dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate,Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate,Alkyl N,N,N', N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate).

More typically hydroxy protecting groups include subtituted methylethers, substituted benzyl ethers, silyl ethers, and esters includingsulfonic acid esters, still more typically, trialkylsilyl ethers,tosylates and acetates.

Typical 1,2- and 1,3-diol protecting groups are described in Greene atpages 118-142 and include Cyclic Acetals and Ketals (Methylene,Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); andSilyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene) Derivative,Tetra-t-butoxydisiloxane-1,3-diylidene Derivative, Cyclic Carbonates,Cyclic Boronates, Ethyl Boronate, Phenyl Boronate).

More typically, 1,2- and 1,3-diol protecting groups include those shownin Table 3, still more typically, epoxides and acetonides.

Typical amino protecting groups are described in Greene at pages 315-385and include Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl,9(2-Sulfo)fluoroenylmethyl, 9-(2,7-Dibromo)fluorenylmethyl,2,7-Di-t-buthyl-9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)!methyl,4-Methoxyphenacyl); Substituted Ethyl (2,2,2-Trichoroethyl,2-Trimethylsilylethyl, 2-Phenylethyl, 1-(1-Adamantyl)-1-methylethyl,1,1-Dimethyl-2-haloethyl, 1,1-Dimethyl-2,2-dibromoethyl,1,1-Dimethyl-2,2,2-trichloroethyl, 1-Methyl-1-(4-biphenylyl)ethyl,1-(3,5-Di-t-butylphenyl)-1-methylethyl, 2-(2'- and 4'-Pyridyl)ethyl,2-(N,N-Dicyclohexylcarboxamido)ethyl, t-Butyl, 1-Adamantyl, Vinyl,Allyl, 1-Isopropylallyl, Cinnamyl, 4-Nitrocinnamyl, 8-Quinolyl,N-Hydroxypiperidinyl, Alkyldithio, Benzyl, p-Methoxybenzyl,p-Nitrobenzyl, p-Bromobenzyl, p-Chorobenzyl, 2,4-Dichlorobenzyl,4-Methylsulfinylbenzyl, 9-Anthrylmethyl, Diphenylmethyl); Groups WithAssisted Cleavage (2-Methylthioethyl, 2-Methylsulfonylethyl,2-(p-Toluenesulfonyl)ethyl, 2-(1,3-Dithianyl)!methyl,4-Methylthiophenyl, 2,4-Dimethylthiophenyl, 2-Phosphonioethyl,2-Triphenylphosphonioisopropyl, 1,1-Dimethyl-2-cyanoethyl,m-Choro-p-acyloxybenzyl, p-(Dihydroxyboryl)benzyl,5-Benzisoxazolylmethyl, 2-(Trifluoromethyl)-6-chromonylmethyl); GroupsCapable of Photolytic Cleavage (m-Nitrophenyl, 3,5-Dimethoxybenzyl,o-Nitrobenzyl, 3,4-Dimethoxy-6-nitrobenzyl,Phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives(Phenothiazinyl-(10)-carbonyl Derivative,N'-p-Toluenesulfonylaminocarbonyl, N'-Phenylaminothiocarbonyl);Miscellaneous Carbamates (t-Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl,Cyclobutyl, Cyclohexyl, Cyclopentyl, Cyclopropylmethyl,p-Decyloxybenzyl, Diisopropylmethyl, 2,2-Dimethoxycarbonylvinyl,o-(N,N-Dimethylcarboxamido)benzyl,1,1-Dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-Dimethylpropynyl,Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl,Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl,1-Methylcyclohexyl, 1-Methyl-1-cyclopropylmethyl,1-Methyl-1-(3,5-dimethoxyphenyl)ethyl,1-Methyl-1-(p-phenylazophenyl)ethyl, 1-Methyl-1-phenylethyl,1-Methyl-1-(4-pyridyl)ethyl, Phenyl, p-(Phenylazo)benzyl,2,4,6-Tri-t-butylphenyl, 4-(Trimethylammonium)benzyl,2,4,6-Trimethylbenzyl); Amides (N-Formyl, N-Acetyl, N-Choroacetyl,N-Trichoroacetyl, N-Trifluoroacetyl, N-Phenylacetyl,N-3-Phenylpropionyl, N-Picolinoyl, N-3-Pyridylcarboxamide,N-Benzoylphenylalanyl Derivative, N-Benzoyl, N-p-Phenylbenzoyl); AmidesWith Assisted Cleavage (N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl,N-Acetoacetyl, (N'-Dithiobenzyloxycarbonylamino)acetyl,N-3-(p-Hydroxyphenyl)propionyl, N-3-(o-Nitrophenyl)propionyl,N-2-Methyl-2-(o-nitrophenoxy)propionyl,N-2-Methyl-2-(o-phenylazophenoxy)propionyl, N-4-Chlorobutyryl,N-3-Methyl-3-nitrobutyryl, N-o-Nitrocinnamoyl, N-AcetylmethionineDerivative, N-o-Nitrobenzoyl, N-o-(Benzoyloxymethyl)benzoyl,4,5-Diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-Phthalimide,N-Dithiasuccinoyl, N-2,3-Diphenylmaleoyl, N-2,5-Dimethylpyrrolyl,N-1,1,4,4-Tetramethyldisilylazacyclopentane Adduct, 5-Substituted1,3-Dimethyl-1,3,5-triazacyclohexan-2-one, 5-Substituted1,3-Dibenzyl-1,3,5-triazacyclohexan-2-one, 1-Substituted3,5-Dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-Methyl, N-Allyl,N- 2-(Trimethylsilyl)ethoxy!methyl, N-3-Acetoxypropyl,N-(1-Isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary AmmoniumSalts, N-Benzyl, N-Di(4-methoxyphenyl)methyl, N-5-Dibenzosuberyl,N-Triphenylmethyl, N-(4-Methoxyphenyl)diphenylmethyl,N-9-Phenylfluorenyl, N-2,7-Dichloro-9-fluorenylmethylene,N-Ferrocenylmethyl, N-2-Picolylamine N'-Oxide); Imine Derivatives(N-1,1-Dimethylthiomethylene, N-Benzylidene, N-p-methoxybenylidene,N-Diphenylmethylene, N- (2-Pyridyl)mesityl!methylene,N,(N',N'-Dimethylaminomethylene, N,N'-Isopropylidene,N-p-Nitrobenzylidene, N-Salicylidene, N-5-Chlorosalicylidene,N-(5-Chloro-2-hydroxyphenyl)phenylmethylene, N-Cyclohexylidene); EnamineDerivative (N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives(N-Borane Derivatives, N-Diphenylborinic Acid Derivative, N-Phenyl(pentacarbonylchromium- or -tungsten)!carbenyl, N-Copper or N-ZincChelate); N-N Derivatives (N-Nitro, N-Nitroso, N-Oxide); N-P Derivatives(N-Diphenylphosphinyl, N-Dimethylthiophosphinyl,N-Diphenylthiophosphinyl, N-Dialkyl Phosphoryl, N-Dibenzyl Phosphoryl,N-Diphenyl Phosphoryl); N-Si Derivatives; N-S Derivatives; N-SulfenylDerivatives (N-Benzenesulfenyl, N-o-Nitrobenzenesulfenyl,N-2,4-Dinitrobenzenesulfenyl, N-Pentachlorobenzenesulfenyl,N-2-nitro-4-methoxybenzenesulfenyl, N-Triphenylmethylsulfenyl,N-3-Nitropyridinesulfenyl); andN-Sulfonyl Derivatives(N-p-Toluenesulfonyl, N-Benzenesulfonyl,N-2,3,6-Trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-Trimethoxybenzenesulfonyl,N-2,6-Dimethyl-4-methoxybenzenesulfonyl, N-Pentamethylbenzenesulfonyl,N-2,3,5,6,-Tetramethyl-4-methoxybenzenesulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6- Trimethylbenzenesulfonyl,N-2,6-Dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-Pentamethylchroman-6-sulfonyl, N-Methanesulfonyl,N-β-Trimethylsilyethanesulfonyl, N-9-Anthracenesulfonyl, N-4-(4',8'-Dimethoxynaphthylmethyl)benzenesulfonyl, N-Benzylsulfonyl,N-Trifluoromethylsulfonyl, N-Phenacylsulfonyl).

More typically, amino protecting groups include carbamates and amides,still more typically, N-acetyl groups.

Groups capable of biological cleavage typically include common prodrugs.A large number of such groups are described in "Design of Prodrugs",Hans Bundgaard (Elsevier, N.Y., 1985, ISBN 0-444-80675-X) (Bundgaard)and will not be detailed here. In particular, Bundgaard, pages 1 to 92describe prodrugs and their biological cleavage reactions for a numberof functional group types. Prodrugs for carboxyl and hydroxyl groups aredetailed in Bundgaard at pages 3 to 10, for amides, imides and otherNH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, andcyclic prodrugs, as for example when J and L are taken together, atpages 62 to 70.

Additional exemplary J and L groups are described below in Table 13.

The compounds of this invention contains 0 to 6 R₆ groups, typically 0to 3 R₆ groups.

Another embodiment of the invention is directed to compositionscomprising compounds of the formula: ##STR24## wherein: Y isindependently --N(R₁)--, --N(R₁)--SO₂ --, or --N(R₁)--CO--;

E and U are independently H, or --(CR₁ R₁)_(m1) --W₁, with the provisothat at least one of E and U is --(CR₁ R₁)_(m1) --W₁ ;

G and T are independently --(CR₁ R₁)_(m1) --W₁, or --(CR₁ R₁)_(m1)--C(R₁)(W₁)(W₂), with the proviso that:

when E is --(CR₁ R₁)_(m1) --W₁, then G is --(CR₁ R₁)_(m1) --W₁, and

when U is --(CR₁ R₁)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁ and G andT may be the same or different;

J and L are independently H, N₃, --OR₂, --N(R₂)(R₂), or --N(R₂)(R₃),wherein R₂ is H, or PRT with the proviso that at least one of J and L is--OR₂ ; or J and L are taken together to form an epoxide, or a cyclicprotecting group;

W₁ is W₂ or W₃ ;

W₂ is carbocycle or heterocycle, with the proviso that each W₂ isindependently substituted with 0 to 3 R₅ groups;

W₃ is alkyl, alkenyl, or alkynyl, with the proviso that each W₃ isindependently substituted with 0 to 3 R₆ groups;

R₁ is R₃ or R₆ ;

R₃ is H or R₄ ;

R₄ is alkyl;

R₅ is R₆, or R₇, with the proviso that each R₇ is independentlysubstituted with 0 to 3 R₆ groups;

R₆ is --O--(antigenic polypeptide), --N(R₃)-(antigenic polypeptide),--C(O)O--(antigenic polypeptide), --C(O)N(R₃)-(antigenic polypeptide),F, Cl, Br, I, --CN, N₃, --NO₂, --OR₃, --N(R₃)(R₃), --SR₃, --O--C(O)R₄,--N(R₃)--C(O)R₄, --C(O)N(R₃)(PRT), --C(O)N(PRT)₂, --C(O)N(R₃)₂,--C(O)OR₃, --OPRT, --N(PRT)₂, --C(NR₃)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)),--C(N(R₃))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂), --C(N(PRT))(N(PRT)₂),--N(R₃)(PRT), --S(PRT), carbocycle or heterocycle;

R₇ is alkyl, alkenyl, or alkynyl;

Each m₁ is independently an integer from 0 to 3; and with the provisothat the compound, taken as a whole, contains 0 to 16 R₆ groups, andthat each E, G, T, and U, taken individually, contain 0 to 8 R₆ groups.

Typically, in this embodiment Y is --N(R₃)--, more typically, Y is--N(H)--. The preferred embodiments of E, G, J, L, T, discussed above,are also preferred in each of these embodiments.

Stereochemistry

Formulas herein that do not depict stereochemistry are intended toinclude all possible stereochemistries. For example, formulas I, II, andIII do not depict stereochemistry for the sulfoxide or groups E, G, J,L, T, and U. All possible stereochemistries of these groups areintended. Table 1 lists specifically each of these intendedstereochemistries for groups E, G, J, L, T and V. Depending on thechoice of substituents, certain of the individual compounds of Table 1may be redundant, being identical to one another by symmetry options.

The designation α indicates that the group is projected behind the planeof the page and the designation , β indicates that the group projectsabove the plane of the page. For example, structure "a" in Table 10 isαQ_(b), αO--Q_(c), αQ_(d), αQ_(e), βO--Q_(f), αQ_(g), structure "k" isαQ_(b), αO--Q_(c), αQ_(d), βQ_(e), βO--Q_(f), βQ_(g), and structure "q"is βQ_(b), βO--Q_(c), βQ_(d), αO--Q_(e), αO--Q_(f), αQ.

If each of the substituents E, G, T and U are independently selectedfrom the structures of Table 12; and if each of the substituents J and Lare independently selected from the structures of Table 13, then the 36structures of Table 10 each represent a typical stereochemistry.

One typical group of stereochemistries is represented by structures"a"-"k" in Table 10. These structures are available, inter alia fromL-mannitol as described by Schemes 1-3, and 5-6 below.

Another typical group of stereochemistries is represented by structures"l"-"v" in Table 10. These structures are available, inter alia, fromD-mannitol as described by Schemes 1-3, and 5-6 below.

Another typical group of stereochemistries is represented by structures"w"-"B" in Table 10. These structures are available, inter alia, from L-or D-mannitol as described by Scheme 4 below.

Another typical group of stereochemistries is represented by structures"C"-"J" in Table 10. These structures are available, inter alia frominostitol derivatives known in the art as described by Scheme 7 below.

One preferred stereochemistry is that shown in structure "k" of Table10, αQ_(b), αO-Q_(c), αQ_(d), βQ_(e), βO-Q_(f), βQ_(g) or αE, αO-G, αJ,βL, βO-T, βU.

When group Q_(a) is --S(O)-- (structure "b" from Table 11) then,depending on the choice of the remaining substituents and the ringsubstituent stereochemistries, an additional stereocenter is introduced.Each of the two possible sulfoxide diastereomers is intended, neitherbeing uniquely preferred.

The compounds of the invention can exist as optical isomers at anyasymmetric atoms. For example, the chiral centers designated by "*" inthe depictions can exist as stereoisomers. Both racemic anddiasteromeric mixtures of these isomers which may exist for certaincompounds, as well as the individual optical isomers isolated orsynthesized, being resolved or substantially (>90%) free of theirenantiomeric or diastereomeric partners, are all within the scope of theinvention. The racemic mixtures are separated into their individual,substantially optically pure isomers through well-known techniques suchas, for example, the separation of diastereomeric salts formed withoptically active adjuncts, e.g., acids or bases followed by conversionback to the optically active substances. A large number of suchtechniques are described in "Enantiomers, Racemates, and resolutions",Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger PublishingCompany, Malabar, Fla., 1991, ISBN 0-89464-618-4). In particular, Part2, Resolution of Enantiomer Mixture, pages 217-435; more particularly,section 4, Resolution by Direct Crystallization, pages 217-251, section5, Formation and Separation of Diastereomers, pages 251-369, section 6,Crystallization-Induced Asymmetric Transformations, pages 369-378, andsection 7, Experimental Aspects and Art of Resolutions, pages 378-435;still more particularly, section 5.1.4, Resolution of Alcohols.Transformation of Alcohols into Salt-Forming Derivatives, pages 263-266,section 5.2.3 Covalent Derivatives of Alcohols, Thiols, and Phenols,pages 332-335, and section 5.2.7, Chromatographic Behavior of CovalentDiastereomers, pages 348-354, are cited as examples of the skill of theart. In most instances, the desired optical isomer is synthesized bymeans of stereoselective reactions, beginning with the appropriatestereoisomer of the desired starting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. For example, ene-amine tautomers can exist for imidazole,guanine, amidine, and tetrazole systems and all the possible tautomericforms of either are within the scope of the invention.

The compositions of this invention optionally comprise pharmaceuticallyacceptable non-toxic salts of the compounds herein, containing, forexample, Na⁺, Li⁺, K⁺, Ca⁺⁺ and Mg⁺⁺. Such salts may include thosederived by combination of appropriate cations such as alkali andalkaline earth metal ions or ammonium and quaternary amino ions with anacid anion moiety, typically a carboxylic acid, phenol, or the like.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂ SO₄ amino acids such as glutamicacid or aspartic acid, lysine, hydroxylysine, arginine or histidine, ororganic sulfonic acids, with basic centers, typically amines, pyridine,or the like. Finally, it is to be understood that the compositionsherein comprise compounds of the invention in their un-ionized, as wellas zwitterionic form, as appropriate.

Oxidation and alkylation of amine groups of the compositions of theinvention to form N-oxides and quaternary ammonium salts, respectively,is also contemplated within the scope of the invention.

Exemplary Enumerated Compounds.

By way of example and not limitation, a number of exemplary specificallyenumerated compounds of the invention are listed below in Table 14.Generally, the compositions of the invention are depicted by thestructures of formulas I, II, and III.

The compounds in the Table 14 exemplary list are designated by analphanumerical format in which the first field is the seven memberedring structure of formulas I, II or III as numbered in Table 10. Thesecond field represents Q_(a), the third field represents Q_(b), thefourth field represents Q_(c), the fifth field represents Q_(d), thesixth field represents Q_(e), the seventh field represents Q_(f), andthe eight field represents Q_(g), each attached by a covalent bond tothe ring system as depicted in Table 10. Fields are separated byperiods.

The ring structures of Table 10 have labels Q_(a), Q_(b), Q_(c), Q_(d),Q_(e), Q_(f), and Q_(g) as shown. The groups shown in Table 11 are Q_(a)groups. The groups shown in Table 12 are the Qb, Qc, Qf and Qg groups.The groups shown in Table 13 are the Qd and Qe groups.

The following process is followed to determine the identity of a Table14 compound.

1. The first letter from left to right is one of the ring systems shownin Table 10, designated a-z and A-Y. This is the cyclic structure whichis substituted by the 7 substituents specified by the remaining 7designation codes.

2. The second letter encodes the Qa group of the Table 10 structuresspecified in the first code letter. The Qa groups are listed in Table11, where they are shown with flanking Qi sites. The Qi sites arelocated at the ring carbon atoms occupied by the Q_(g) and Q_(b)substituents. Q₁ is not a depiction of a group or bond but is onlyintended to show orientation of Q_(a).

3. The third letter (or combination of letters not separated by aperiod) encodes the Q_(b) group of the Table 10 ring structure specifiedby the first letter in the compound code. Refer to Table 12 and selectthe encoded Q_(b) group. The "Q₂ " designation in the Table 12 groupsdepicts the site at which the Q_(b) group is bonded to the ring carbonatom; Q₂ does not stand for any group or bond, but instead (like Q₁) isonly intended to aid in determining the substitution site.

4. The fourth letter (or combination of letters not separated by aperiod) encodes the Qc group of the designated ring structure. Again,refer to Table 12 to select the encoded group. Q₂ has the same meaningas with Q_(b) except that the bonding site is the oxygen atom shown inthe Table 10 structure encoded by the first letter.

5. The fifth letter encodes Q_(d). It is determined by reference toTable 13 in the same general fashion as was done for Q_(a), Q_(b) andQ_(c). Q₃ in Table 13 similarly is the designation of ring carbon atomsite, but does not represent a bond or group in its own right.

6. The sixth letter encodes Q_(e). It is decoded from Table 13 in thesame was as Q_(d).

7. The seventh and eight letters (or combinations of letters) encodeQ_(f) and Q_(g), respectively. They are decoded from Table 12 in thesame fashion as Q_(b) and Q_(c).

By way of example, three compounds having the designationk.c.a.a.b.b.a.a, k.b.a.a.c.c.a.a, and q.a.aN.J.b.c.a.aA are shown below.##STR25##

                  TABLE 10                                                        ______________________________________                                        Seven Membered Heterocycles                                                   ______________________________________                                                                       a                                               ##STR26##                     b                                               ##STR27##                     c                                               ##STR28##                     d                                               ##STR29##                     e                                               ##STR30##                     f                                               ##STR31##                     g                                               ##STR32##                     h                                               ##STR33##                     i                                               ##STR34##                     j                                               ##STR35##                     k                                               ##STR36##                                                                     ##STR37##                     m                                               ##STR38##                     n                                               ##STR39##                     o                                               ##STR40##                     p                                               ##STR41##                     q                                               ##STR42##                     r                                               ##STR43##                     s                                               ##STR44##                     t                                               ##STR45##                     u                                               ##STR46##                     v                                               ##STR47##                     w                                               ##STR48##                     x                                               ##STR49##                     y                                               ##STR50##                     z                                               ##STR51##                     A                                               ##STR52##                     B                                               ##STR53##                     C                                               ##STR54##                     D                                               ##STR55##                     E                                               ##STR56##                     F                                               ##STR57##                     G                                               ##STR58##                     H                                               ##STR59##                     I                                               ##STR60##                     J                                               ##STR61##                     K                                               ##STR62##                     L                                               ##STR63##                     M                                               ##STR64##                     N                                               ##STR65##                     O                                               ##STR66##                     P                                               ##STR67##                     Q                                               ##STR68##                     R                                               ##STR69##                     S                                               ##STR70##                     T                                               ##STR71##                     U                                               ##STR72##                     V                                               ##STR73##                     W                                               ##STR74##                     X                                               ##STR75##                     Y                                              ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                        Qa groups                                                                     ______________________________________                                         ##STR76##                                                                    ______________________________________                                    

                                      TABLE 12                                    __________________________________________________________________________    Q.sub.b, Q.sub.c, Q.sub.f and Q.sub.g groups                                  __________________________________________________________________________     ##STR77##                                                                     ##STR78##                                                                     ##STR79##                                                                     ##STR80##                                                                     ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                     ##STR95##                                                                     ##STR96##                                                                     ##STR97##                                                                     ##STR98##                                                                     ##STR99##                                                                     ##STR100##                                                                    ##STR101##                                                                    ##STR102##                                                                    ##STR103##                                                                    ##STR104##                                                                    ##STR105##                                                                    ##STR106##                                                                    ##STR107##                                                                    ##STR108##                                                                    ##STR109##                                                                    ##STR110##                                                                    ##STR111##                                                                    ##STR112##                                                                    ##STR113##                                                                    ##STR114##                                                                    ##STR115##                                                                    ##STR116##                                                                    ##STR117##                                                                    ##STR118##                                                                    ##STR119##                                                                    ##STR120##                                                                    ##STR121##                                                                    ##STR122##                                                                    ##STR123##                                                                    ##STR124##                                                                    ##STR125##                                                                    ##STR126##                                                                    ##STR127##                                                                    ##STR128##                                                                    ##STR129##                                                                    ##STR130##                                                                    ##STR131##                                                                    ##STR132##                                                                    ##STR133##                                                                    ##STR134##                                                                    ##STR135##                                                                    ##STR136##                                                                    ##STR137##                                                                    ##STR138##                                                                    ##STR139##                                                                    ##STR140##                                                                    ##STR141##                                                                    ##STR142##                                                                    ##STR143##                                                                    ##STR144##                                                                    ##STR145##                                                                    ##STR146##                                                                    ##STR147##                                                                    ##STR148##                                                                    ##STR149##                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                    ##STR153##                                                                    ##STR154##                                                                    ##STR155##                                                                    ##STR156##                                                                    ##STR157##                                                                    ##STR158##                                                                    ##STR159##                                                                    ##STR160##                                                                    ##STR161##                                                                    ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                    ##STR165##                                                                    ##STR166##                                                                    ##STR167##                                                                    ##STR168##                                                                    ##STR169##                                                                    ##STR170##                                                                    ##STR171##                                                                    ##STR172##                                                                    ##STR173##                                                                    ##STR174##                                                                    ##STR175##                                                                    ##STR176##                                                                   __________________________________________________________________________

                  TABLE 13                                                        ______________________________________                                        Q.sub.d and Q.sub.e groups                                                    ______________________________________                                         ##STR177##                                                                    ##STR178##                                                                   ______________________________________                                    

                                      TABLE 14                                    __________________________________________________________________________    Exemplary Compounds of the Invention                                          __________________________________________________________________________    k.c.a.a.a.b.a.a                                                                           k.c.a.a.a.b.a.aA                                                                          k.c.a.a.a.b.a.aG                                                                          k.c.a.a.a.b.e.a                           k.c.a.a.a.b.e.aA                                                                          k.c.a.a.a.b.e.aG                                                                          k.c.a.a.a.b.m.a                                                                           k.c.a.a.a.b.m.aA                          k.c.a.a.a.b.m.aG                                                                          k.c.a.a.a.b.ao.a                                                                          k.c.a.a.a.b.o.aA                                                                          k.c.a.a.a.b.o.aG                          k.c.a.a.a.b.E.a                                                                           k.c.a.a.a.b.E.aA                                                                          k.c.a.a.a.b.E.aG                                                                          k.c.a.a.a.b.R.a                           k.c.a.a.a.b.R.aA                                                                          k.c.a.a.a.b.R.aG                                                                          k.c.a.a.a.b.aw.a                                                                          k.c.a.a.a.b.aw.aA                         k.c.a.a.a.b.aw.aG                                                                         k.c.a.a.a.b.aA.a                                                                          k.c.a.a.a.b.aA.aA                                                                         k.c.a.a.a.b.aA.aG                         k.c.a.a.a.b.aG.a                                                                          k.c.a.a.a.b.aG.aA                                                                         k.c.a.a.a.b.aG.aG                                                                         k.c.a.a.b.a.a.a                           k.c.a.a.b.a.a.aA                                                                          k.c.a.a.b.a.a.aG                                                                          k.c.a.a.b.a.e.a                                                                           k.c.a.a.b.a.e.aA                          k.c.a.a.b.a.e.aG                                                                          k.c.a.a.b.a.m.a                                                                           k.c.a.a.b.a.m.aA                                                                          k.c.a.a.b.a.m.aG                          k.c.a.a.b.a.ao.a                                                                          k.c.a.a.b.a.o.aA                                                                          k.c.a.a.b.a.o.aG                                                                          k.c.a.a.b.a.E.a                           k.c.a.a.b.a.E.aA                                                                          k.c.a.a.b.a.E.aG                                                                          k.c.a.a.b.a.R.a                                                                           k.c.a.a.b.a.R.aA                          k.c.a.a.b.a.R.aG                                                                          k.c.a.a.b.a.aw.a                                                                          k.c.a.a.b.a.aw.aA                                                                         k.c.a.a.b.a.aw.aG                         k.c.a.a.b.a.aA.a                                                                          k.c.a.a.b.a.aA.aA                                                                         k.c.a.a.b.a.aA.aG                                                                         k.c.a.a.b.a.aG.a                          k.c.a.a.b.a.aG.aA                                                                         k.c.a.a.b.a.aG.aG                                                                         k.c.a.a.b.b.a.a                                                                           k.c.a.a.b.b.a.aA                          k.c.a.a.b.b.a.aG                                                                          k.c.a.a.b.b.e.a                                                                           k.c.a.a.b.b.e.aA                                                                          k.c.a.a.b.b.e.aG                          k.c.a.a.b.b.m.a                                                                           k.c.a.a.b.b.m.aA                                                                          k.c.a.a.b.b.m.aG                                                                          k.c.a.a.b.b.ao.a                          k.c.a.a.b.b.o.aA                                                                          k.c.a.a.b.b.o.aG                                                                          k.c.a.a.b.b.E.a                                                                           k.c.a.a.b.b.E.aA                          k.c.a.a.b.b.E.aG                                                                          k.c.a.a.b.b.R.a                                                                           k.c.a.a.b.b.R.aA                                                                          k.c.a.a.b.b.R.aG                          k.c.a.a.b.b.aw.a                                                                          k.c.a.a.b.b.aw.aA                                                                         k.c.a.a.b.b.aw.aG                                                                         k.c.a.a.b.b.aA.a                          k.c.a.a.b.b.aA.aA                                                                         k.c.a.a.b.b.aA.aG                                                                         k.c.a.a.b.b.aG.a                                                                          k.c.a.a.b.b.aG.aA                         k.c.a.a.b.b.aG.aG                                                                         k.c.a.e.a.b.a.a                                                                           k.c.a.e.a.b.a.aA                                                                          k.c.a.e.a.b.a.aG                          k.c.a.e.a.b.e.a                                                                           k.c.a.e.a.b.e.aA                                                                          k.c.a.e.a.b.e.aG                                                                          k.c.a.e.a.b.m.a                           k.c.a.e.a.b.m.aA                                                                          k.c.a.e.a.b.m.aG                                                                          k.c.a.e.a.b.ao.a                                                                          k.c.a.e.a.b.o.aA                          k.c.a.e.a.b.o.aG                                                                          k.c.a.e.a.b.E.a                                                                           k.c.a.e.a.b.E.aA                                                                          k.c.a.e.a.b.E.aG                          k.c.a.e.a.b.R.a                                                                           k.c.a.e.a.b.R.aA                                                                          k.c.a.e.a.b.R.aG                                                                          k.c.a.e.a.b.aw.a                          k.c.a.e.a.b.aw.aA                                                                         k.c.a.e.a.b.aw.aG                                                                         k.c.a.e.a.b.a.A.a                                                                         k.c.a.e.a.b.aA.aA                         k.c.a.e.a.b.aA.aG                                                                         k.c.a.e.a.h.aG.a                                                                          k.c.a.e.a.b.aG.aA                                                                         k.c.a.e.a.b.aG.aG                         k.c.a.e.b.a.a.a                                                                           k.c.a.e.b.a.a.aA                                                                          k.c.a.e.b.a.a.aG                                                                          k.c.a.e.b.a.e.a                           k.c.a.e.b.a.e.aA                                                                          k.c.a.e.b.a.e.aG                                                                          k.c.a.e.b.a.m.a                                                                           k.c.a.e.b.a.m.aA                          k.c.a.e.b.a.m.aG                                                                          k.c.a.e.b.a.ao.a                                                                          k.c.a.e.b.a.o.aA                                                                          k.c.a.e.b.a.o.aG                          k.c.a.e.b.a.E.a                                                                           k.c.a.e.b.a.E.aA                                                                          k.c.a.e.b.a.E.aG                                                                          k.c.a.e.b.a.R.a                           k.c.a.e.b.a.R.aA                                                                          k.c.a.e.b.a.R.aG                                                                          k.c.a.e.b.a.aw.a                                                                          k.c.a.e.b.a.aw.aA                         k.c.a.e.b.a.aw.aG                                                                         k.c.a.e.b.a.aA.a                                                                          k.c.a.e.b.a.aA.aA                                                                         k.c.a.e.b.a.aA.aG                         k.c.a.e.b.a.aG.a                                                                          k.c.a.e.b.a.aG.aA                                                                         k.c.a.e.b.a.aG.aG                                                                         k.c.a.e.b.b.a.a                           k.c.a.e.b.b.a.aA                                                                          k.c.a.e.b.b.a.aG                                                                          k.c.a;e.b.b.e.a                                                                           k.c.a.e.b.b.e.aA                          k.c.a.e.b.b.e.aG                                                                          k.c.a.e.b.b.m.a                                                                           k.c.a.e.b.b.m.aA                                                                          k.c.a.e.b.b.m.aG                          k.c.a.e.b.b.aG.a                                                                          k.c.a.e.b.b.o.aA                                                                          k.c.a.e.b.b.o.aG                                                                          k.c.a.e.b.b.E.a                           k.c.a.e.b.b.E.aA                                                                          k.c.a.e.b.b.E.aG                                                                          k.c.a.e.b.b.R.a                                                                           k.c.a.e.b.b.R.aA                          k.c.a.e.b.b.R.aG                                                                          k.c.a.e.b.b.aw.a                                                                          k.c.a.e.b.b.aw.aA                                                                         k.c.a.e.b.b.aw.aG                         k.c.a.e.b.b.aA.a                                                                          k.c.a.e.b.b.aA.aA                                                                         k.c.a.e.b.b.aA.aG                                                                         k.c.a.e.b.b.aG.a                          k.c.a.e.b.b.aG.aA                                                                         k.c.a.e.b.b.aG.aG                                                                         k.c.a.m.a.b.a.a                                                                           k.c.a.m.a.b.a.aA                          k.c.a.m.a.b.a.aG                                                                          k.c.a.m.a.b.e.a                                                                           k.c.a.m.a.b.e.aA                                                                          k.c.a.m.a.b.e.aG                          k.c.a.m.a.b.m.a                                                                           k.c.a.m.a.b.m.aA                                                                          k.c.a.m.a.b.m.aG                                                                          k.c.a.m.a.b.ao.a                          k.c.a.m.a.b.o.aA                                                                          k.c.a.m.a.b.o.aG                                                                          k.c.a.m.a.b.E.a                                                                           k.c.a.m.a.b.E.aA                          k.c.a.m.a.b.E.aG                                                                          k.c.a.m.a.b.R.a                                                                           k.c.a.m.a.b.R.aA                                                                          k.c.a.m.a.b.R.aG                          k.c.a.m.a.b.aw.a                                                                          k.c.a.m.a.b.aw.aA                                                                         k.c.a.m.a.b.aw.aG                                                                         k.c.a.m.a.b.aA.a                          k.c.a.m.a.b.aA.aA                                                                         k.c.a.m.a.b.aA.aG                                                                         k.c.a.m.a.b.aG.a                                                                          k.c.a.m.a.b.aG.aA                         k.c.a.m.a.b.aG.aG                                                                         k.c.a.m.b.a.a.a                                                                           k.c.a.m.b.a.a.aA                                                                          k.c.a.m.b.a.a.aG                          k.c.a.m.b.a.e.a                                                                           k.c.a.m.b.a.e.aA                                                                          k.c.a.m.b.a.e.aG                                                                          k.c.a.m.b.a.m.a                           k.c.a.m.b.a.m.aA                                                                          k.c.a.m.b.a.m.aG                                                                          k.c.a.m.b.a.ao.a                                                                          k.c.a.m.b.a.o.aA                          k.c.a.m.b.a.o.aG                                                                          k.c.a.m.b.a.E.a                                                                           k.c.a.m.b.a.E.aA                                                                          k.c.a.m.b.a.E.aG                          k.c.a.m.b.a.R.a                                                                           k.c.a.m.b.a.R.aA                                                                          k.c.a.m.b.a.R.aG                                                                          k.c.a.m.b.a.aw.a                          k.c.a.m.b.a.aw.aA                                                                         k.c.a.m.b.a.aw.aG                                                                         k.c.a.m.h.a.aA.a                                                                          k.c.a.m.b.a.aA.aA                         k.c.a.m.b.a.aA.aG                                                                         k.c.a.m.b.a.aG.a                                                                          k.c.a.m.b.a.aG.aA                                                                         k.c.a.m.b.a.aG.aG                         k.c.a.m.b.b.a.a                                                                           k.c.a.m.b.b.a.aA                                                                          k.c.a.m.b.b.a.aG                                                                          k.c.a.m.b.b.e.a                           k.c.a.m.b.b.e.aA                                                                          k.c.a.m.b.b.e.aG                                                                          k.c.a.m.b.b.m.a                                                                           k.c.a.m.b.b.m.aA                          k.c.a.m.b.b.m.aG                                                                          k.c.a.m.b.b.ao.a                                                                          k.c.a.m.b.b.o.aA                                                                          k.c.a.m.b.b.o.aG                          k.c.a.m.b.b.E.a                                                                           k.c.a.m.b.b.E.aA                                                                          k.c.a.m.b.b.E.aG                                                                          k.c.a.m.b.b.R.a                           k.c.a.m.b.b.R.aA                                                                          k.c.a.m.b.b.R.aG                                                                          k.c.a.m.b.b.aw.a                                                                          k.c.a.m.b.b.aw.aA                         k.c.a.m.b.b.aw.aG                                                                         k.c.a.m.b.b.aA.a                                                                          k.c.a.m.b.b.aA.aA                                                                         k.c.a.m.b.b.aA.aG                         k.c.a.m.b.b.aG.a                                                                          k.c.a.m.b.b.aG.aA                                                                         k.c.a.m.b.b.aG.aG                                                                         k.c.a.o.a.b.a.a                           k.c.a.o.a.b.a.aA                                                                          k.c.a.o.a.b.a.aG                                                                          k.c.a.o.a.b.e.a                                                                           k.c.a.d.a.b.e.aA                          k.c.a.o.a.b.e.aG                                                                          k.c.a.o.a.b.m.a                                                                           k.c.a.o.a.b.m.aA                                                                          k.c.a.o.a.b.m.aG                          k.c.a.o.a.b.ao.a                                                                          k.c.a.o.a.b.o.aA                                                                          k.c.a.o.a.b.o.aG                                                                          k.c.a.o.a.b.E.a                           k.c.a.o.a.b.E.aA                                                                          k.c.a.o.a.b.E.aG                                                                          k.c.a.o.a.b.R.a                                                                           k.c.a.o.a.b.R.aA                          k.c.a.o.a.b.R.aG                                                                          k.c.a.o.a.b.aw.a                                                                          k.c.a.o.a.b.aw.aA                                                                         k.c.a.o.a.b.aw.aG                         k.c.a.o.a.b.aA.a                                                                          k.c.a.o.a.b.aA.aA                                                                         k.c.a.o.a.b.aA.aG                                                                         k.c.a.o.a.b.aG.a                          k.c.a.o.a.b.aG.aA                                                                         k.c.a.o.a.b.aG.aG                                                                         k.c.a.o.b.a.a.a                                                                           k.c.a.o.b.a.a.aA                          k.c.a.o.b.a.a.aG                                                                          k.c.a.o.b.a.e.a                                                                           k.c.a.o.b.a.e.aA                                                                          k.c.a.o.b.a.e.aG                          k.c.a.o.b.a.m.a                                                                           k.c.a.o.b.a.m.aA                                                                          k.c.a.o.b.a.m.aG                                                                          k.c.a.o.b.a.ao.a                          k.c.a.o.b.a.o.aA                                                                          k.c.a.o.b.a.o.aG                                                                          k.c.a.o.b.a.E.a                                                                           k.c.a.o.b.a.E.aA                          k.c.a.o.b.a.E.aG                                                                          k.c.a.o.b.a.R.a                                                                           k.c.a.o.b.a.R.aA                                                                          k.c.a.o.b.a.R.aG                          k.c.a.o.b.a.aw.a                                                                          k.c.a.o.b.a.aw.aA                                                                         k.c.a.o.b.a.aw.aG                                                                         k.c.a.o.b.a.aA.a                          k.c.a.o.b.a.aA.aA                                                                         k.c.a.o.b.a.aA.aG                                                                         k.c.a.o.b.a.aG.a                                                                          k.c.a.o.b.a.aG.aA                         k.c.a.o.b.a.aG.aG                                                                         k.c.a.o.b.b.a.a                                                                           k.c.a.o.b.b.a.aA                                                                          k.c.a.o.b.b.a.aG                          k.c.a.o.b.b.e.a                                                                           k.c.a.o.b.b.e.aA                                                                          k.c.a.o.b.b.e.aG                                                                          k.c.a.o.b.b.m.a                           k.c.a.o.b.b.m.aA                                                                          k.c.a.o.b.b.m.aG                                                                          k.c.a.o.b.b.ao.a                                                                          k.c.a.o.b.b.o.aA                          k.c.a.o.b.b.o.aG                                                                          k.c.a.o.b.b.E.a                                                                           k.c.a.o.b.b.E.aA                                                                          k.c.a.o.b.b.E.aG                          k.c.a.o.b.b.R.a                                                                           k.c.a.o.b.b.R.aA                                                                          k.c.a.o.b.b.R.aG                                                                          k.c.a.o.b.b.aw.a                          k.c.a.o.b.b.aw.aA                                                                         k.c.a.o.b.b.aw.aG                                                                         k.c.a.o.b.b.aA.a                                                                          k.c.a.o.b.b.aA.aA                         k.c.a.o.b.b.aA.aG                                                                         k.c.a.o.b.b.aG.a                                                                          k.c.a.o.b.b.aG.aA                                                                         k.c.a.o.b.b.aG.aG                         k.c.a.E.a.b.a.a                                                                           k.c.a.E.a.b.a.aA                                                                          k.c.a.E.a.b.a.aG                                                                          k.c.a.E.a.b.e.a                           k.c.a.E.a.b.e.aA                                                                          k.c.a.E.a.b.e.aG                                                                          k.c.a.E.a.b.m.a                                                                           k.c.a.E.a.b.m.aA                          k.c.a.E.a.b.m.aG                                                                          k.c.a.E.a.b.ao.a                                                                          k.c.a.E.a.b.o.aA                                                                          k.c.a.E.a.b.o.aG                          k.c.a.E.a.b.E.a                                                                           k.c.a.E.a.b.E.aA                                                                          k.c.a.E.a.b.E.aG                                                                          k.c.a.E.a.b.R.a                           k.c.a.E.a.b.R.aA                                                                          k.c.a.E.a.b.R.aG                                                                          k.c.a.E.a.b.aw.a                                                                          k.c.a.E.a.b.aw.aA                         k.c.a.E.a.b.aw.aG                                                                         k.c.a.E.a.b.aA.a                                                                          k.c.a.E.a.b.aA.aA                                                                         k.c.a.E.a.b.aA.aG                         k.c.a.E.a.b.aG.a                                                                          k.c.a.E.a.b.aG.aA                                                                         k.c.a.E.a.b.aG.aG                                                                         k.c.a.E.b.a.a.a                           k.c.a.E.b.a.a.aA                                                                          k.c.a.E.b.a.a.aG                                                                          k.c.a.E.b.a.e.a                                                                           k.c.a.E.b.a.e.aA                          k.c.a.E.b.a.e.aG                                                                          k.c.a.E.b.a.m.a                                                                           k.c.a.E.b.a.m.aA                                                                          k.c.a.E.b.a.m.aG                          k.c.a.E.b.a.ao.a                                                                          k.c.a.F.b.a.o.aA                                                                          k.c.a.E.b.a.o.aG                                                                          k.c.a.E.b.a.E.a                           k.c.a.E.b.a.E.aA                                                                          k.c.a.E.b.a.E.aG                                                                          k.c.a.E.b.a.R.a                                                                           k.c.a.E.b.a.R:aA                          k.c.a.E.b.a.R.aG                                                                          k.c.a.E.b.a.aw.a                                                                          k.c.a.E.b.a.aw.aA                                                                         k.c.a.E.b.a.aw.aG                         k.c.a.E.b.a.aA.a                                                                          k.c.a.E.b.a.aA.aA                                                                         k.c.a.E.b.a.aA.aG                                                                         k.c.a.E.b.a.aG.a                          k.c.a.E.b.a.aG.aA                                                                         k.c.a.E.b.a.aG.aG                                                                         k.c.a.E.b.b.a.a                                                                           k.c.a.E.b.b.a.aA                        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                           k.c.a.E.b.b.R.a                                                                           k.c.a.E.b.b.R.aA                                                                          k.c.a.E.b.b.R.aG                          k.c.a.E.b.b.aw.a                                                                          k.c.a.E.b.b.aw.aA                                                                         k.c.a.E.b.b.aw.aG                                                                         k.c.a.E.b.b.aA.a                          k.c.a.E.b.b.aA.aA                                                                         k.c.a.E.b.b.aA.aG                                                                         k.c.a.E.b.b.aG.a                                                                          k.c.a.E.b.b.aG.aA                         k.c.a.E.b.b.aG.aG                                                                         k.c.a.R.a.b.a.a                       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k.c.a.R.a.b.E.aA                                                                          k.c.a.R.a.b.E.aG                          k.c.a.R.a.b.R.a                                                                           k.c.a.R.a.b.R.aA                                                                          k.c.a.R.a.b.R.aG                                                                          k.c.a.R.a.b.aw.a                          k.c.a.R.a.b.aw.aA                                                                         k.c.a.R.a.b.aw.aG                                                                         k.c.a.R.a.b.aA.a                                                                          k.c.a.R.a.b.aA.aA                         k.c.a.R.a.b.aA.aG                                                                         k.c.a.R.a.b.aG.a                                                                          k.c.a.R.a.b.aG.aA                                                                         k.c.a.R.a.b.aG.aG                         k.c.a.R.b.a.a.a                                                                           k.c.a.R.b.a.a.aA                                                                          k.c.a.R.b.a.a.aG                                                                          k.c.a.R.b.a.e.a                           k.c.a.R.b.a.e.aA                                                                          k.c.a.R.b.a.e.aG                                                                          k.c.a.R.b.a.m.a                                                                           k.c.a.R.b.a.m.aA                          k.c.a.R.b.a.m.aG                                                                          k.c.a.R.b.a.ao.a                                                                          k.c.a.R.b.a.o.aA                                                                          k.c.a.R.b.a.o.aG                        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                           k.c.a.R.b.a.aG.aA                                                                         k.c.a.R.b.a.aG.aG                                                                         k.c.a.R.b.b.a.a                           k.c.a.R.b.b.a.aA                                                                          k.c.a.R.b.b.a.aG                                                                          k.c.a.R.b.b.e.a                                                                           k.c.a.R.b.b.e.aA                          k.c.a.R.b.b.e.aG                                                                          k.c.a.R.b.b.m.a                                                                           k.c.a.R.b.b.m.aA                                                                          k.c.a.R.b.b.m.aG                          k.c.a.R.b.b.ao.a                                                                          k.c.a.R.b.b.o.aA                                                                          k.c.a.R.b.b.o.aG                                                                          k.c.a.R.b.b.E.a                           k.c.a.R.b.b.E.aA                                                                          k.c.a.R.b.b.F.aG                                                                          k.c.a.R.b.b.R.a                                                                           k.c.a.R.b.b.R.aA                          k.c.a.R.b.b.R.aG                                                                          k.c.a.R.b.b.aw.a                                                                          k.c.a.R.b.b.aw.aA                                                                         k.c.a.R.b.b.aw.aG                         k.c.a.R.b.b.aA.a                                                                          k.c.a.R.b.b.aA.aA                                                                         k.c.a.R.b.b.aA.aG                                                                         k.c.a.R.b.b.aG.a                          k.c.a.R.b.b.aG.aA                                                                         k.c.a.R.b.b.aG.aG                                                                         k.c.a.aw.a.b.a.a                                                                          k.c.a.aw.a.b.a.aA                         k.c.a.aw.a.b.a.aG                                                                         k.c.a.aw.a.b.e.a                                                                          k.c.a.aw.a.b.e.aA                                                                         k.c.a.aw.a.b.e.aG                         k.c.a.aw.a.b.m.a                                                                          k.c.a.aw.a.b.m.aA                                                                         k.c.a.aw.a.b.m.aG                                                                         k.c.a.aw.a.b.ao.a                         k.c.a.aw.a.b.o.aA                                                                         k.c.a.aw.a.b.o.aG                                                                         k.c.a.aw.a.b.E.a                                                                          k.c.a.aw.a.b.E.aA                         k.c.a.aw.a.b.E.aG                                                                         k.c.a.aw.a.b.R.a                                                                          k.c.a.aw.a.b.R.aA                                                                         k.c.a.aw.a.b.R.aG                         k.c.a.aw.a.b.aw.a                                                                         k.c.a.aw.a.b.aw.aA                                                                        k.c.a.aw.a.b.aw.aG                                                                        k.c.a.aw.a.b.aA.a                         k.c.a.aw.a.b.aA.aA                                                                        k.c.a.aw.a.b.aA.aG                                                                        k.c.a.aw.a.b.aG.a                                     k.c.a.aw.a.b.aG.aA                                                                        k.c.a.aw.a.b.aG.aG                                                                        k.c.a.aw.b.a.a.a                                                                          k.c.a.aw.b.a.a.aA                         k.c.a.aw.b.a.a.aG                                                                         k.c.a.aw.b.a.e.a                                                                          k.c.a.aw.b.a.e.aA                                                                         k.c.a.aw.b.a.e.aG                         k.c.a.aw.b.a.m.a                                                                          k.c.a.aw.b.a.m.aA                                                                         k.c.a.aw.b.a.m.aG                                                                         k.c.a.aw.b.a.aG.a                         k.c.a.aw.b.a.o.aA                                                                         k.c.a.aw.b.a.o.aG                                                                         k.c.a.aw.h.a.E.a                                                                          k.c.a.aw.b.a.E.aA                         k.c.a.aw.b.a.E.aG                                                                         k.c.a.aw.b.a.R.a                                                                          k.c.a.aw.b.a.R.aA                                                                         k.c.a.aw.b.a.R.aG                         k.c.a.aw.b.a.aw.a                                                                         k.c.a.aw.b.a.aw.aA                                                                        k.c.a.aw.b.a.aw.aG                                                                        k.c.a.aw.b.a.aA.a                         k.c.a.aw.b.a.aA.aA                                                                        k.c.a.aw.b.a.aA.aG                                                                        k.c.a.aw.b.a.aG.a                                     k.c.a.aw.b.a.aG.aA                                                                        k.c.a.aw.b.a.aG.aG                                                                        k.c.a.aw.b.b.a.a                                                                          k.c.a.aw.b.b.a.aA                         k.c.a.aw.b.b.a.aG                                                                         k.c.a.aw.b.b.e.a                                                                          k.c.a.aw.b.b.e.aA                                                                         k.c.a.aw.b.b.e.aG                         k.c.a.aw.b.b.m.a                                                                          k.c.a.aw.b.b.m.aA                                                                         k.c.a.aw.b.b.m.aG                                                                         k.c.a.aw.b.b.ao.a                         k.c.a.aw.b.b.o.aA                                                                         k.c.a.aw.b.b.o.aG                                                                         k.c.a.aw.b.b.E.a                                                                          k.c.a.aw.b.b.F.aA                         k.c.a.aw.b.b.E.aG                                                                         k.c.a.aw.b.b.R.a                                                                          k.c.a.aw.b.b.R.aA                                                                         k.c.a.aw.b.b.R.aG                         k.c.a.aw.b.b.aw.a                                                                         k.c.a.aw.b.b.aw.aA                                                                        k.c.a.aw.b.b.aw.aG                                                                        k.c.a.aw.b.b.aA.a                         k.c.a.aw.b.b.aA.aA                                                                        k.c.a.aw.b.b.aA.aG                                                                        k.c.a.aw.b.b.aG.a                                     k.c.a.aw.b.b.aG.aA                                                                        k.c.a.aw.b.b.aG.aG                                                                        k.c.a.aA.a.b.a.a                                                                          k.c.a.aA.a.b.a.aA                         k.c.a.aA.a.b.a.aG                                                                         k.c.a.aA.a.b.e.a                                                                          k.c.a.aA.a.b.e.aA                                                                         k.c.a.aA.a.b.e.aG                         k.c.a.aA.a.b.m.a                                                                          k.c.a.aA.a.b.m.aA                                                                         k.c.a.aA.a.b.m.aG                                                                         k.c.a.aA.a.b.ao.a                         k.c.a.aA.a.b.o.aA                                                                         k.c.a.aA.a.b.o.aG                                                                         k.c.a.aA.a.b.E.a                                                                          k.c.a.aA.a.b.E.aA                         k.c.a.aA.a.b.E.aG                                                                         k.c.a.aA.a.b.R.a                                                                          k.c.a.aA.a.b.R.aA                                                                         k.c.a.aA.a.b.R.aG                         k.c.a.aA.a.b.aw.a                                                                         k.c.a.aA.a.b.aw.aA                                                                        k.c.a.aA.a.b.aw.aG                                                                        k.c.a.aA.a.b.aA.a                         k.c.a.aA.a.b.aA.aA                                                                        k.c.a.aA.a.b.aA.aG                                                                        k.c.a.aA.a.b.aG.a                                     k.c.a.aA.a.b.aG.aA                                                                        k.c.a.aA.a.b.aG.aG                                                                        k.c.a.aA.b.a.a.a                                                                          k.c.a.aA.b.a.a.aA                         k.c.a.aA.b.a.a.aG                                                                         k.c.a.aA.b.a.e.a                                                                          k.c.a.aA.b.a.e.aA                                                                         k.c.a.aA.b.a.e.aG                         k.c.a.aA.b.a.m.a                                                                          k.c.a.aA.b.a.m.aA                                                                         k.c.a.aA.b.a.m.aG                                                                         k.c.a.aA.b.a.ao.a                         k.c.a.aA.b.a.o.aA                                                                         k.c.a.aA.b.a.o.aG                                                                         k.c.a.aA.b.a.E.a                                                                          k.c.a.aA.b.a.E.aA                         k.c.a.aA.b.a.E.aG                                                                         k.c.a.aA.b.a.R.a                                                                          k.c.a.aA.b.a.R.aA                                                                         k.c.a.aA.b.a.R.aG                         k.c.a.aA.b.a.aw.a                                                                         k.c.a.aA.b.a.aw.aA                                                                        k.c.a.aA.b.a.aw.aG                                                                        k.c.a.aA.b.a.aA.a                         k.c.a.aA.b.a.aA.aA                                                                        k.c.a.aA.b.a.aA.aG                                                                        k.c.a.aA.b.a.aG.a                                     k.c.a.aA.b.a.aG.aA                                                                        k.c.a.aA.b.a.aG.aG                                                                        k.c.a.aA.b.b.a.a                                                                          k.c.a.aA.b.b.a.aA                         k.c.a.aA.b.b.a.aG                                                                         k.c.a.aA.b.b.e.a                                                                          k.c.a.aA.b.b.e.aA                                                                         k.c.a.aA.b.b.e.aG                         k.c.a.aA.b.b.m.a                                                                          k.c.a.aA.b.b.m.aA                                                                         k.c.a.aA.b.b.m.aG                                                                         k.c.a.aA.b.b.ao.a                         k.c.a.aA.b.b.o.aA                                                                         k.c.a.aA.b.b.o.aG                                                                         k.c.a.aA.b.b.E.a                                                                          k.c.a.aA.b.b.E.aA                         k.c.a.aA.b.b.E.aG                                                                         k.c.a.aA.b.b.R.a                                                                          k.c.a.aA.b.b.R.aA                                                                         k.c.a.aA.b.b.R.aG                         k.c.a.aA.b.b.aw.a                                                                         k.c.a.aA.b.b.aw.aA                                                                        k.c.a.aA.b.b.aw.aG                                                                        k.c.a.aA.b.b.aA.a                         k.c.a.aA.b.b.aA.aA                                                                        k.c.a.aA.b.b.aA.aG                                                                        k.c.a.aA.b.b.aG.a                                     k.c.a.aA.b.b.aG.aA                                                                        k.c.a.aA.b.b.aG.aG                                                k.c.a.aG.a.b.a.a                                                                          k.c.a.aG.a.b.a.aA                                                                         k.c.a.aG.a.b.a.aG                                                                         k.c.a.aG.a.b.e.a                          k.c.a.aG.a.b.e.aA                                                                         k.c.a.aG.a.b.e.aG                                                                         k.c.a.aG.a.b.m.a                                                                          k.c.a.aG.a.b.m.aA                         k.c.a.aG.a.b.m.aG                                                                         k.c.a.aG.a.b.ao.a                                                                         k.c.a.aG.a.b.o.aA                                                                         k.c.a.aG.a.b.o.aG                         k.c.a.aG.a.b.E.a                                                                          k.c.a.aG.a.b.E.aA                                                                         k.c.a.aG.a.b.E.aG                                                                         k.c.a.aG.a.b:R.a                          k.c.a.aG.a.b.R.aA                                                                         k.c.a.aG.a.b.R.aG                                                                         k.c.a.aG.a.b.aw.a                                     k.c.a.aG.a.b.aw.aA                                                                        k.c.a.aG.a.b.aw.aG                                                                        k.c.a.aG.a.b.aA.a                                     k.c.a.aG.a.b.aA.aA                                                                        k.c.a.aG.a.b.aA.aG                                                                        k.c.a.aG.a.b.aG.a                                     k.c.a.aG.a.b.aG.aA                                                                        k.c.a.aG.a.b.aG.aG                                                                        k.c.a.aG.b.a.a.a                                                                          k.c.a.aG.b.a.a.aA                         k.c.a.aG.b.a.a.aG                                                                         k.c.a.aG.b.a.e.a                                                                          k.c.a.aG.b.a.e.aA                                                                         k.c.a.aG.b.a.e.aG                         k.c.a.aG.b.a.m.a                                                                          k.c.a.aG.b.a.m.aA                                                                         k.c.a.aG.b.a.m.aG                                                                         k.c.a.aG.b.a.ao.a                         k.c.a.aG.b.a.o.aA                                                                         k.c.a.aG.b.a.o.aG                                                                         k.c.a.aG.b.a.E.a                                                                          k.c.a.aG.b.a.E.aA                         k.c.a.aG.b.a.E.aG                                                                         k.c.a.aG.b.a.R.a                                                                          k.c.a.aG.b.a.R.aA                                                                         k.c.a.aG.b.a.R.aG                         k.c.a.aG.b.a.aw.a                                                                         k.c.a.aG.b.a.aw.aA                                                                        k.c.a.aG.b.a.aw.aG                                                                        k.c.a.aG.b.a.aA.a                         k.c.a.aG.b.a.aA.aA                                                                        k.c.a.aG.b.a.aA.aG                                                                        k.c.a.aG.b.a.aG.a                                     k.c.a.aG.b.a.aG.aA                                                                        k.c.a.aG.b.a.aG.aG                                                                        k.c.a.aG.b.b.a.a                                                                          k.c.a.aG.b.b.a.aA                         k.c.a.aG.b.b.a.aG                                                                         k.c.a.aG.b.b.e.a                                                                          k.c.a.aG.b.b.e.aA                                                                         k.c.a.aG.b.b.e.aG                         k.c.a.aG.b.b.m.a                                                                          k.c.a.aG.b.b.m.aA                                                                         k.c.a.aG.b.b.m.aG                                                                         k.c.a.aG.b.b.ao.a                         k.c.a.aG.b.b.d.aA                                                                         k.c.a.a.G.b.b.o.aG                                                                        k.c.a.aG.b.b.E.a                                                                          k.c.a.aG.b.b.E.aA                         k.c.a.aG.b.b.E.aG                                                                         k.c.a.aG.b.b.R.a                                                                          k.c.a.aG.b.b.R.aA                                                                         k.c.a.aG.b.b.R.aG                         k.c.a.aG.b.b.aw.a                                                                         k.c.a.aG.b.b.aw.aA                                                                        k.c.a.aG.b.b.aw.aG                                                                        k.c.a.aG.b.b.aA.a                         k.c.a.aG.b.b.aA.aA                                                                        k.c.a.aG.b.b.aA.aG                                                                        k.c.a.aG.b.b.aG.a                                     k.c.a.aG.b.b.aG.aA                                                                        k.c.a.aG.b.b.aG.aG                                                                        k.c.aA.a.a.b.a.a                                                                          k.c.aA.a.a.b.a.aA                         k.c.aA.a.a.b.a.aG                                                                         k.c.aA.a.a.b.e.a                                                                          k.c.aA.a.a.b.e.aA                                                                         k.c.aA.a.a.b.e.aG                         k.c.aA.a.a.b.m.a                                                                          k.c.aA.a.a.b.m.aA                                                                         k.c.aA.a.a.b.m.aG                                                                         k.c.aA.a.a.b.ao.a                         k.c.aA.a.a.b.o.aA                                                                         k.c.aA.a.a.b.o.aG                                                                         k.c.aA.a.a.b.E.a                                                                          k.c.aA.a.a.b.E.aA                         k.c.aA.a.a.b.E.aG                                                                         k.c.aA.a.a.b.R.a                                                                          k.c.aA.a.a.b.R.aA                                                                         k.c.aA.a.a.b.R.aG                         k.c.aA.a.a.b.aw.a                                                                         k.c.aA.a.a.b.aw.aA                                                                        k.c.aA.a.a.b.aw.aG                                                                        k.c.aA.a.a.b.aA.a                         k.c.aA.a.a.b.aA.aA                                                                        k.c.aA.a.a.b.aA.aG                                                                        k.c.aA.a.a.b.aG.a                                     k.c.aA.a.a.b.aG.aA                                                                        k.c.aA.a.a.b.aG.aG                                                                        k.c.aA.a.b.a.a.a                                                                          k.c.aA.a.b.a.a.aA                         k.c.aA.a.b.a.a.aG                                                                         k.c.aA.a.b.a.e.a                                                                          k.c.aA.a.b.a.e.aA                                                                         k.c.aA.a.b.a.e.aG                         k.c.aA.a.b.a.m.a                                                                          k.c.aA.a.b.a.m.aA                                                                         k.c.aA.a.b.a.m.aG                                                                         k.c.aA.a.b.a.ao.a                         k.c.aA.a.b.a.o.aA                                                                         k.c.aA.a.b.a.o.aG                                                                         k.c.aA.a.b.a.F.a                                                                          k.c.aA.a.b.a.E.aA                         k.c.aA.a.b.a.E.aG                                                                         k.c.aA.a.b.a.R.a                                                                          k.c.aA.a.b.a.R.aA                                                                         k.c.aA.a.b.a.R.aG                         k.c.aA.a.b.a.aw.a                                                                         k.c.aA.a.b.a.aw.aA                                                                        k.c.aA.a.b.a.aw.aG                                                                        k.c.aA.a.b.a.aA.a                         k.c.aA.a.b.a.aA.aA                                                                        k.c.a.A.a.b.a.aA.aG                                                                       k.c.aA.a.b.a.aG.a                                     k.c.aA.a.b.a.aG.aA                                                                        k.c.aA.a.b.a.aG.aG                                                                        k.c.aA.a.b.b.a.a                                                                          k.c.aA.a.b.b.a.aA                         k.c.aA.a.b.b.a.aG                                                                         k.c.aA.a.b.b.e.a                                                                          k.c.aA.a.b.b.e.aA                                                                         k.c.aA.a.b.b.e.aG                         k.c.aA.a.b.b.m.a                                                                          k.c.aA.a.b.b.m.aA                                                                         k.c.aA.a.b.b.m.aG                                                                         k.c.aA.a.b.b.ao.a                         k.c.aA.a.b.b.o.aA                                                                         k.c.aA.a.b.b.o.aG                                                                         k.c.aA.a.b.b.E.a                                                                          k.c.aA.a.b.b.E.aA                         k.c.aA.a.b.b.E.aG                                                                         k.c.aA.a.b.b.R.a                                                                          k.c.aA.a.b.b.R.aA                                                                         k.c.aA.a.b.b.R.aG                         k.c.aA.a.b.b.aw.a                                                                         k.c.aA.a.b.b.aw.aA                                                                        k.c.aA.a.b.b.aw.aG                                                                        k.c.aA.a.b.b.aA.a                         k.c.aA.a.b.b.aA.aA                                                                        k.c.aA.a.b.b.aA.aG                                                                        k.c.aA.a.b.b.aG.a                                     k.c.aA.a.b.b.aG.aA                                                                        k.c.aA.a.b.b.aG.aG                                                                        k.c.aA.e.a.b.a.a                                                                          k.c.aA.e.a.b.a.aA                         k.c.aA.e.a.b.a.aG                                                                         k.c.aA.e.a.b.e.a                                                                          k.c.aA.e.a.b.e.aA                                                                         k.c.aA.e.a.b.e.aG                         k.c.aA.e.a.b.m.a                                                                          k.c.aA.e.a.b.m.aA                                                                         k.c.aA.e.a.b.m.aG                                                                         k.c.aA.e.a.b.ao.a                         k.c.aA.e.a.b.o.aA                                                                         k.c.aA.e.a.b.o.aG                                                                         k.c.aA.e.a.b.E.a                                                                          k.c.aA.e.a.b.E.aA                         k.c.aA.e.a.b.E.aG                                                                         k.c.aA.e.a.b.R.a                                                                          k.c.aA.e.a.b.R.aA                                                                         k.c.aA.e.a.b.R.aG                         k.c.aA.e.a.b.aw.a                                                                         k.c.aA.e.a.b.aw.aA                                                                        k.c.aA.e.a.b.aw.aG                                                                        k.c.aA.e.a.b.aA.a                         k.c.aA.e.a.b.aA.aA                                                                        k.c.aA.e.a.b.aA.aG                                                                        k.c.aA.e.a.b.aG.a                                     k.c.aA.e.a.b.aG.aA                                                                        k.c.aA.e.a.b.aG.aG                                                                        k.c.aA.e.b.a.a.a                                                                          k.c.aA.e.b.a.a.a.A                        k.c.aA.e.b.a.a.aG                                                                         k.c.aA.e.b.a.e.a                                                                          k.c.aA.e.b.a.e.aA                                                                         k.c.aA.e.b.a.e.aG                         k.c.aA.et.a.m.a                                                                           k.c.aA.e.b.a.m.aA                                                                         k.c.aA.e.b.a.m.aG                                                                         k.c.aA.e.b.a.ao.a                         k.c.aA.e.b.a.o.aA                                                                         k.c.aA.e.b.a.o.aG                                                                         k.c.aA.e.b.a.E.a                                                                          k.c.aA.e.b.a.E.aA                         k.c.aA.e.b.a.E.aG                                                                         k.c.aA.e.b.a.R.a                                                                          k.c.aA.e.b.a.R.aA                                                                         k.c.aA.e.b.a.R.aG                         k.c.aA.e.b.a.aw.a                                                                         k.c.aA.e.b.a.aw.aA                                                                        k.c.aA.e.b.a.aw.aG                                                                        k.c.aA.e.b.a.aA.a                         k.c.aA.e.b.a.aA.aA                                                                        k.c.aA.e.b.a.aA.aG                                                                        k.c.aA.e.b.a.aG.a                                     k.c.aA.e.b.a.aG.aA                                                                        k.c.aA.e.b.a.aG.aG                                                                        k.c.aA.e.b.b.a.a                                                                          k.c.aA.e.b.b.a.aA                         k.c.aA.e.b.b.a.aG                                                                         k.c.aA.e.b.b.e.a                                                                          k.c.aA.e.b.b.e.aA                                                                         k.c.aA.e.b.b.e.aG                         k.c.aA.e.b.b.m.a                                                                          k.c.aA.e.b.b.m.aA                                                                         k.c.aA.e.b.b.m.aG                                                                         k.c.aA.e.b.b.ao.a                         k.c.aA.e.b.b.o.aA                                                                         k.c.aA.e.b.b.o.aG                                                                         k.c.aA.e.b.b.E.a                                                                          k.c.aA.e.b.b.E.aA                         k.c.aA.e.b.b.E.aG                                                                         k.c.aA.e.b.k.R.a                                                                          k.c.aA.e.b.b.R.aA                                                                         k.c.aA.e.b.b.R.aG                         k.c.aA.e.b.b.aw.a                                                                         k.c.aA.e.b.b.aw.aA                                                                        k.c.aA.e.b.b.aw.aG                                                                        k.c.aA.e.b.b.aA.a                         k.c.aA.e.b.b.aA.aA                                                                        k.c.aA.e.b.b.aA.aG                                                                        k.c.aA.e.b.b.aG.a                                     k.c.aA.e.b.b.aG.aA                                                                        k.c.aA.e.b.b.aG.aG                                                                        k.c.aA.m.a.b.a.a                                                                          k.c.aA.m.a.b.a.aA                         k.c.aA.m.a.b.a.aG                                                                         k.c.aA.m.a.b.e.a                                                                          k.c.aA.m.a.b.e.aA                                                                         k.c.aA.m.a.b.e.aG                         k.c.aA.m.a.b.m.a                                                                          k.c.aA.m.a.b.m.aA                                                                         k.c.aA.m.a.b.m.aG                                                                         k.c.aA.m.a.b.ao.a                         k.c.aA.m.a.b.o.aA                                                                         k.c.aA.m.a.b.o.aG                                                                         k.c.aA.m.a.b.E.a                                                                          k.c.aA.m.a.b.E.aA                         k.c.aA.m.a.b.E.aG                                                                         k.c.aA.m.a.b.R.a                                                                          k.c.aA.m.a.b.R.aA                                     k.c.aA.m.a.b.R.aG                                                                         k.c.aA.m.a.b.aw.a                                                                         k.c.aA.m.a.b.aw.aA                                    k.c.aA.m.a.h.aw.aG      k.c.aA.m.a.b.aA.a                                     k.c.aA.m.a.b.aA.aA      k.c.aA.m.a.b.aA.aG                                    k.c.aA.m.a.b.aG.a                                                                         k.c.aA.m.a.b.aG.aA                                                k.c.aA.m.a.b.aG.aG                                                                        k.c.aA.m.b.a.a.a                                                                          k.c.aA.m.b.a.a.aA                                                                         k.c.aA.m.b.a.a.aG                         k.c.aA.m.b.a.e.a                                                                          k.c.aA.m.b.a.e.aA                                                                         k.c.aA.m.b.a.e.aG                                                                         k.c.aA.m.b.a.m.a                          k.c.aA.m.b.a.m.aA                                                                         k.c.aA.m.b.a.m.aG                                                                         k.c.aA.m.b.a.ao.a                                                                         k.c.aA.m.b.a.o.aA                         k.c.aA.m.b.a.o.aG                                                                         k.c.aA.m.b.a.E.a                                                                          k.c.aA.m.b.a.E.aA                                                                         k.c.aA.m.h.a.E.aG                         k.c.aA.m.b.a.R.a                                                                          k.c.aA.m.b.a.R.aA                                                                         k.c.aA.m.b.a.R.aG                                                                         k.c.aA.m.b.a.aw.a                         k.c.aA.m.b.a.aw.aA      k.c.aA.m.b.a.aw.aG                                    k.c.aA.m.b.a.aA.a                                                                         k.c.aA.m.b.a.aA.aA                                                k.c.aA.m.b.a.aA.aG      k.c.aA.m.b.a.aG.a                                     k.c.aA.m.b.a.aG.aA      k.c.aA.m.b.a.aG.aG                                                                        k.c.aA.m.b.b.a.a                          k.c.aA.m.b.b.a.aA                                                                         k.c.aA.m.b.b.a.aG                                                                         k.c.aA.m.b.b.e.a                                                                          k.c.aA.m.b.b.e.aA                         k.c.aA.m.b.b.e.aG                                                                         k.c.aA.m.b.b.m.a                                                                          k.c.aA.m.b.b.m.aA                                     k.c.aA.m.b.b.m.aG                                                                         k.c.aA.m.b.b.ao.a                                                                         k.c.aA.m.b.b.o.aA                                                                         k.c.aA.m.b.b.6.aG                         k.c.aA.m.b.b.E.a                                                                          k.c.aA.m.b.b.E.aA                                                                         k.c.aA.m.b.b.E.aG                                                                         k.c.aA.m.b.b.R.a                          k.c.aA.m.b.b.R.aA                                                                         k.c.aA.m.b.b.R.aG                                                                         k.c.aA.m.b.b.aw.a                                     k.c.aA.m.b.b.aw.aA      k.c.aA.m.b.b.aw.aG                                    k.c.aA.m.b.b.aA.a                                                                         k.c.aA.m.b.b.aA.aA                                                k.c.aA.m.b.b.aA.aG      k.c.aA.m.b.b.aG.a                                     k.c.aA.m.b.b.aG.aA      k.c.aA.m.b.b.aG.aG                                                                        k.c.aA.9.a.b.a.a                          k.c.aA.o.a.b.a.aA                                                                         k.c.aA.o.a.b.a.aG                                                                         k.c.aA.o.a.b.e.a                                                                          k.c.aA.o.a.b.e.aA                         k.c.aA.o.a.b.e.aG                                                                         k.c.aA.o.a.b.m.a                                                                          k.c.aA.o.a.b.m.aA                                                                         k.c.aA.o.a.b.m.aG                         k.c.aA.o.a.b.ao.a                                                                         k.c.aA.o.a.b.o.aA                                                                         k.c.aA.o.a.b.o.aG                                                                         k.c.aA.o.a.b.E.a                          k.c.aA.o.a.b.E.aA                                                                         k.c.aA.o.a.b.E.aG                                                                         k.c.aA.o.a.b.R.a                                                                          k.c.aA.o.a.b.R.aA                         k.c.aA.o.a.b.R.aG                                                                         k.c.aA.o.a.b.aw.a                                                                         k.c.aA.o.a.b.aw.aA                                    k.c.aA.o.a.b.aw.aA                                                                        k.c.aA.o.a.b.aA.a                                                                         k.c.aA.o.a.b.aA.aA                                    k.c.aA.o.a.b.aA.aG                                                                        k.c.aA.o.a.b.aG.a                                                                         k.c.aA.o.a.b.aG.aA                                    k.c.aA.o.a.b.aG.aG                                                                        k.c.aA.o.b.a.a.a                                                                          k.c.aA.o.b.a.a.aA                                                                         k.c.aA.o.b.a.a.aG                         k.c.aA.o.b.a.e.a                                                                          k.c.aA.o.b.a.e.aA                                                                         k.c.aA.o.b.a.e.aG                                                                         k.c.aA.o.b.a.m.a                          k.c.aA.o.b.a.m.aA                                                                         k.c.aA.o.b.a.m.aG                                                                         k.c.aA.o.b.a.ao.a                                                                         k.c.aA.o.b.a.o.aA                         k.c.aA.o.b.a.o.aG                                                                         k.c.aA.o.b.a.E.a                                                                          k.c.aA.o.b.a.E.aA                                                                         k.c.aA.o.b.a.E.aG                         k.c.aA.o.b.a.R.a                                                                          k.c.aA.o.b.a.R.aA                                                                         k.c.aA.o.b.a.R.aG                                                                         k.c.aA.o.b.a.aw.a                         k.c.aA.o.b.a.aw.aA                                                                        k.c.aA.o.b.a.aw.aG                                                                        k.c.aA.o.b.a.aA.a                                     k.c.aA.o.b.a.aA.aA                                                                        k.c.aA.o.b.a.aA.aG                                                                        Lc.aA.o.b.a.aG.a                                      k.c.aA.o.b.a.aG.aA                                                                        k.c.aA.o.b.a.aG.aG                                                                        k.c.aA.o.b.b.a.a                                                                          k.c.aA.o.b.b.a.aA                         k.c.aA.o.b.b.a.aG                                                                         k.c.a.A.o.b.b.e.a                                                                         k.c.aA.o.b.b.e.aA                                                                         k.c.aA.o.b.b.e.aG                         k.c.aA.o.b.b.m.a                                                                          k.c.aA.o.b.b.m.aA                                                                         k.c.aA.o.b.b.m.aG                                                                         k.c.aA.o.b.b.ao.a                         k.c.aA.o.b.b.o.aA                                                                         k.c.aA.o.b.b.o.aG                                                                         k.c.aA.o.b.b.E.a                                                                          k.c.aA.o.b.b.E.aA                         k.c.aA.o.b.b.E.aG                                                                         k.c.aA.o.b.b.R.a                                                                          k.c.aA.o.b.b.R.aA                                                                         k.c.aA.o.b.b.R.aG                         k.c.aA.o.b.b.aw.a                                                                         k.c.aA.o.b.b.aw.aA                                                                        k.c.aA.o.b.b.aw.aG                                                                        k.c.aA.o.b.b.aA.a                         k.c.aA.o.b.b.aA.aA                                                                        k.c.aA.o.b.b.aA.aG                                                                        k.c.aA.o.b.b.aG.a                                     k.c.aA.o.b.b.aG.aA                                                                        k.c.aA.o.b.b.aG.aG                                                                        k.c.aA.E.a.b.a.a                                                                          k.c.aA.E.a.b.a.aA                         k.c.aA.E.a.b.a.aG                                                                         k.c.aA.E.a.b.e.a                                                                          k.c.aA.E.a.b.e.aA                                                                         k.c.aA.E.a.b.e.aG                         k.c.aA.E.a.b.m.a                                                                          k.c.aA.E.a.b.m.aA                                                                         k.c.aA.E.a.b.m.aG                                                                         k.c.aA.E.a.b.ao.a                         k.c.aA.E.a.b.o.aA                                                                         k.c.aA.E.a.b.o.aG                                                                         k.c.aA.E.a.b.E.a                                                                          k.c.aA.E.a.b.E.aA                         k.c.aA.E.a.b.E.aG                                                                         k.c.aA.E.a.b.R.a                                                                          k.c.aA.E.a.b.R.aA                                                                         k.c.aA.E.a.b.R.aG                         k.c.aA.E.a.b.aw.a                                                                         k.c.aA.E.a.b.aw.aA                                                                        k.c.aA.E.a.b.aw.aG                                                                        k.c.aA.E.a.b.aA.a                         k.c.aA.E.a.b.aA.aA                                                                        k.c.aA.E.a.b.aA.aG                                                                        k.c.aA.E.a.b.aG.a                                     k.c.aA.E.a.b.aG.aA                                            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k.c.aA.E.b.b.o.aA                                                                         k.c.aA.E.b.b.o.aG                                                                         k.c.aA.E.b.b.E.a                                                                          k.c.aA.E.b.b.E.aA                         k.c.aA.E.b.b.E.aG                                                                         k.c.aA.E.b.b.R.a                                                                          k.c.aA.E.b.b.R.aA                                                                         k.c.aA.E.b.b.R.aG                         k.c.aA.E.b.b.aw.a                                                                         k.c.aA.E.b.b.aw.aA                                                                        k.c.aA.E.b.b.aw.aG                                                                        k.c.aA.E.b.b.aA.a                         k.c.aA.E.b.b.aA.aA                                               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k.c.aA.R.b.a.m.aA                                                                         k.c.aA.R.b.a.m.aG                                                                         k.c.aA.R.b.a.ao.a                         k.c.aA.R.b.a.o.aA                                                                         k.c.aA.R.b.a.o.aG                                                                         k.c.aA.R.b.a.E.a                                                                          k.c.aA.R.b.a.E.aA                         k.c.aA.R.b.a.E.aG                                                                         k.c.aA.R.b.a.R.a                                                                          k.c.aA.R.b.a.R.aA                                                                         k.c.aA.R.b.a.R.aG                         k.c.aA.R.b.a.aw.a                                                                         k.c.aA.R.b.a.aw.aA                                                                        k.c.aA.R.b.a.aw.aG                                                                        k.c.aA.R.b.a.aA.a                         k.c.aA.R.b.a.aA.aA                                                                        k.c.aA.R.b.a.aA.aG                                                                        k.c.aA.R.b.a.aG.a                                     k.c.aA.R.b.a.aG.aA                                                                        k.c.aA.R.b.a.aG.aG                                                                        k.c.aA.R.b.b.a.a                                                                          k.c.aA.R.b.b.a.aA                         k.c.aA.R.b.b.a.aG                                                                         k.c.aA.R.b.b.e.a                                                                          k.c.aA.R.b.b.e.aA                                                                         k.c.aA.R.b.b.e.aG                         k.c.aA.R.b.b.m.a                                                                          k.c.aA.R.b.b.m.aA                                                                         k.c.aA.R.b.b.m.aG                                                                         k.c.aA.R.b.b.ao.a                         k.c.aA.R.b.b.o.aA                                                                         k.c.aA.R.b.b.o.aG                                                                         k.c.aA.R.b.b.E.a                                                                          k.c.aA.R.b.b.E.aA                         k.c.aA.R.b.b.E.aG                                                                         k.c.aA.R.b.b.R.a                                                                          k.c.aA.R.b.b.R.aA                                                                         k.c.aA.R.b.b.R.aG                         k.c.aA.R.b.b.aw.a                                                                         k.c.aA.R.b.b.aw.aA                                                                        k.c.aA.R.b.b.aw.aG                                                                        k.c.aA.R.b.b.aA.a                         k.c.aA.R.b.b.aA.aA                                                                        k.c.aA.R.b.b.aA.aG                                                                        k.c.aA.R.b.b.aG.a                                     k.c.aA.R.b.b.aG.aA                                                                        k.c.aA.R.b.b.aG.aG                                                                        k.c.aA.aw.a.b.a.a                                     k.c.aA.aw.a.b.a.aA                                                                        k.c.aA.aw.a.b.a.aG                                                                        k.c.aA.aw.a.b.e.a                                     k.c.aA.aw.a.b.e.aA                                                                        k.c.aA.aw.a.b.e.aG                                                                        k.c.aA.aw.a.b.m.a                                     k.c.aA.aw.a.b.m.aA      k.c.aA.aw.a.b.m.aG                                    k.c.aA.aw.a.b.ao.a                                                                        k.c.aA.aw.a.b.o.aA                                                                        k.c.aA.aw.a.b.o.aG                                                                        k.c.aA.aw.a.b.E.a                         k.c.aA.aw.a.b.E.aA                                                                        k.c.aA.aw.a.b.E.aG                                                                        k.c.aA.aw.a.b.R.a                                     k.c.aA.aw.a.b.R.aA                                                                        k.c.aA.aw.a.b.R.aG                                                                        k.c.aA.aw.a.b.aw.a                                    k.c.aA.aw.a.b.aw.aA     k.c.aA.aw.a.b.aw.aG                                   k.c.aA.aw.a.b.aA.a                                                                        k.c.aA.aw.a.b.aA.aA                                               k.c.aA.aw.a.b.aA.aG     k.c.aA.aw.a.b.aG.a                                    k.c.aA.aw.a.b.aG.aA     k.c.aA.aw.a.b.aG.aG                                   k.c.aA.aw.b.a.a.a                                                                         k.c.aA.aw.b.a.a.aA                                                                        k.c.aA.aw.b.a.a.aG                                                                        k.c.aA.aw.b.a.e.a                         k.c.aA.aw.b.a.e.aA                                                                        k.c.aA.aw.b.a.e.aG                                                                        k.c.aA.aw.b.a.m.a                                     k.c.aA.aw.b.a.m.aA      k.c.aA.aw.b.a.m.aG                                    k.c.aA.aw.b.a.ao.a                                                                        k.c.aA.aw.b.a.o.aA                                                                        k.c.aA.aw.b.a.o.aG                                                                        k.c.aA.aw.b.a.E.a                         k.c.aA.aw.b.a.E.aA                                                                        k.c.aA.aw.b.a.E.aG                                                                        k.c.aA.aw.b.a.R.a                                     k.c.aA.aw.b.a.R.aA                                                                        k.c.aA.aw.b.a.R.aG                                                                        k.c.aA.aw.b.a.aw.a                                    k.c.aA.aw.b.a.aw.aA     k.c.aA.aw.b.a.aw.aG                                   k.c.aA.aw.b.a.aA.a                                               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                                                  k.c.aA.aw.b.b.o.aG                                                                        k.c.aA.aw.b.b.E.a                         k.c.aA.aw.b.b.E.aA                                                                        k.c.aA.aw.b.b.E.aG                                                                        k.c.aA.aw.b.b.R.a                                     k.c.aA.aw.b.b.R.aA                                                                        k.c.aA.aw.b.b.R.aG                                                                        k.c.aA.aw.b.b.aw.a                                    k.c.aA.aw.b.b.aw.aA     k.c.aA.aw.b.b.aw.aG                                   k.c.aA.aw.b.b.aA.a                                                                        k.c.aA.aw.b.b.aA.aA                                               k.c.aA.aw.b.b.aA.aG     k.c.aA.aw.b.b.aG.a                                    k.c.aA.aw.b.b.aG.aA     k.c.aA.aw.b.b.aG.aG                                   k.c.aA.aA.a.b.a.a                                                                         k.c.aA.aA.a.b.a.aA                                                                        k.c.aA.aA.a.b.a.aG                                                                        k.c.aA.aA.a.b.e.a                         k.c.aA.aA.a.b.e.aA                                                                        k.c.aA.aA.a.b.e.aG                                                                        k.c.aA.aA.a.b.m.a                                     k.c.aA.aA.a.b.m.aA      k.c.aA.aA.a.b.m.aG                                    k.c.aA.aA.a.b.ao.a                                                                        k.c.aA.aA.a.b.o.aA                                                                        k.c.aA.aA.a.b.o.aG                                                                        k.c.aA.aA.a.b.E.a                         k.c.aA.aA.a.b.E.aA                                                                        k.c.aA.aA.a.b.E.aG                                                                        k.c.aA.aA.a.b.R.a                                     k.c.aA.aA.a.b.R.aA                                                                        k.c.aA.aA.a.b.R.aG                                                                        k.c.aA.aA.a.b.aw.a                                    k.c.aA.aA.a.b.aw.aA     k.c.aA.aA.a.b.aw.aG                                   k.c.aA.aA.a.b.aA.a                                                                        k.c.aA.aA.a.b.aA.aA                                               k.c.aA.aA.a.b.aA.aG     k.c.aA.aA.a.b.aG.a                                    k.c.aA.aA.a.b.aG.aA     k.c.aA.aA.a.b.aG.aG                                   k.c.aA.aA.b.a.a.a                                                                         k.c.aA.aA.b.a.a.aA                                                                        k.c.aA.aA.b.a.a.aG                                                                        k.c.aA.aA.b.a.e.a                         k.c.aA.aA.b.a.e.aA                                                                        k.c.aA.aA.b.a.e.aG                                                                        k.c.aA.aA.b.a.m.a                                     k.c.aA.aA.b.a.m.aA      k.c.aA.aA.b.a.m.aG                                    k.c.aA.aA.b.a.ao.a                                                                        k.c.aA.aA.b.a.o.aA                                                                        k.c.aA.aA.b.a.o.aG                                                                        k.c.aA.aA.b.a.E.a                         k.c.aA.aA.b.a.E.aA                                                                        k.c.aA.aA.b.a.E.aG                                                                        k.c.aA.aA.b.a.R.a                                     k.c.aA.aA.b.a.R.aA                                                                        k.c.aA.aA.b.a.R.aG                                                                        k.c.aA.aA.b.a.aw.a                                    k.c.aA.aA.b.a.aw.aA     k.c.aA.aA.b.a.aw.aG                                   k.c.aA.aA.b.a.aA.a                                                                        k.c.aA.aA.b.a.aA.aA                                               k.c.aA.aA.b.a.aA.aG     k.c.aA.aA.b.a.aG.a                                    k.c.aA.aA.b.a.aG.aA     k.c.aA.aA.b.a.aG.aG                                   k.c.aA.aA.b.b.a.a                                                                         k.c.aA.aA.b.b.a.aA                                                                        k.c.aA.aA.b.b.a.aG                                                                        k.c.aA.aA.b.b.e.a                         k.c.aA.aA.b.b.e.aA                                                                        k.c.aA.aA.b.h.e.aG                                                                        k.c.aA.aA.b.b.m.a                                     k.c.aA.aA.b.b.m.aA      k.c.aA.aA.b.b.m.aG                                    k.c.aA.aA.b.b.ao.a                                                                        k.c.aA.aA.b.b.o.aA                                                                        k.c.aA.aA.b.b.o.aG                                                                        k.c.aA.aA.b.b.E.a                         k.c.aA.aA.b.b.E.aA                                                                        k.c.aA.aA.b.b.E.aG                                                                        k.c.aA.aA.b.b.R.a                                     k.c.aA.aA.b.b.R.aA                                                                        k.c.aA.aA.b.b.R.aG                                                                        k.c.aA.aA.b.b.aw.a                                    k.c.aA.aA.b.b.aw.aA     k.c.aA.aA.b.b.aw.aG                                   k.c.aA.aA.b.b.aA.a                                                                        k.c.aA.aA.b.b.aA.aA                                               k.c.aA.aA.b.b.aA.aG     k.c.aA.aA.b.b.aG.a                                    k.c.aA.aA.b.b.aG.aA     k.c.aA.aA.b.b.aG.aG                                   k.c.aA.aG.a.b.a.a                                                                         k.c.aA.aG.a.b.a.aA                                                                        k.c.aA.aG.a.b.a.aG                                                                        k.c.aA.aG.a.b.e.a                         k.c.aA.aG.a.b.e.aA                                                                        k.c.aA.aG.a.b.e.aG                                                                        k.c.aA.aG.a.b.m.a                                     k.c.aA.aG.a.b.m.aA      k.c.aA.aG.a.b.m.aG                                                                        k.c.aA.aG.a.b.ao.a                        k.c.aA.aG.a.b.o.aA                                                                        k.c.aA.aG.a.b.d.aG                                                                        k.c.aA.aG.a.b.E.a                                     k.c.aA.aG.a.b.E.aA                                                                        k.c.aA.aG.a.b.E.aG                                                                        k.c.aA.aG.a.b.R.a                                     k.c.aA.aG.a.b.R.aA                                                                        k.c.aA.aG.a.b.R.aG                                                                        k.c.aA.aG.a.b.aw.a                                    k.c.aA.aG.a.b.aw.aA     k.c.aA.aG.a.b.aw.aG                                   k.c.aA.aG.a.b.aA.a                                                                        k.c.aA.aG.a.b.aA.aA                                               k.c.aA.aG.a.b.aA.aG     k.c.aA.aG.a.b.aG.a                                    k.c.aA.aG.a.b.aG.aA     k.c.aA.aG.a.b.aG.aG                                   k.c.aA.aG.b.a.a.a                                                                         k.c.aA.aG.b.a.a.aA                                                                        k.c.aA.aG.b.a.a.aG                                                                        k.c.aA.aG.b.a.e.a                         k.c.aA.aG.b.a.e.aA                                                                        k.c.aA.aG.b.a.e.aG                                                                        k.c.aA.aG.b.a.m.a                                     k.c.aA.aG.b.a.m.aA      k.c.aA.aG.b.a.m.aG                                                                        k.c.aA.aG.b.a.ao.a                        k.c.aA.aG.b.a.o.aA                                                                        k.c.aA.aG.b.a.o.aG                                                                        k.c.aA.aG.b.a.E.a                                     k.c.aA.aG.b.a.E.aA                                                                        k.c.aA.aG.b.a.E.aG                                                                        k.c.aA.aG.b.a.R.a                                     k.c.aA.aG.b.a.R.aA                                                                        k.c.aA.aG.b.a.R.aG                                                                        k.c.aA.aG.b.a.aw.a                                    k.c.aA.aG.b.a.aw.aA     k.c.aA.aG.k.a.aw.aG                                   k.c.aA.aG.b.a.aA.a                                                                        k.c.aA.aG.b.a.aA.aA                                               k.c.aA.aG.b.a.aA.aG     k.c.aA.aG.b.a.aG.a                                    k.c.aA.aG.b.a.aw.aA     k.c.aA.aG.b.a.aG.aG                                   k.c.aA.aG.b.b.a.a                                                                         k.c.aA.aG.b.b.a.aA                                                                        k.c.aA.aG.b.b.a.amG                                                                       k.c.aA.aG.b.b.e.a                         k.c.aA.aG.b.b.e.aA                                                                        k.c.aA.aG.b.b.e.aG                                                                        k.c.aA.aG.b.b.m.a                                     k.c.aA.aG.b.b.m.aA      k.c.aA.aG.b.b.m.aG                                                                        k.c.aA.aG.b.b.ao.a                        k.c.aA.aG.b.b.o.aA                                                                        k.c.aA.aG.b.b.o.aG                                                                        k.c.aA.aG.b.b.E.a                                     k.c.aA.aG.b.b.E.aG                                                                        k.c.aA.aG.b.b.E.aG                                                                        k.c.aA.mG.b.b.R.a                                     k.c.aA.aG.b.b.R.aA                                                                        k.c.aA.aG.b.b.R.aG                                                                        k.c.aA.aG.b.b.aw.a                                    k.c.aA.aG.b.b.aw.aA     k.c.aA.aG.b.b.aw.aG                                   k.c.aA.aG.b.b.aA.a                                                                        k.c.aA.aG.b.b.aA.aA                                               k.c.aA.aG.b.b.aA.aG     k.c.aA.aG.b.b.aG.a                                    k.c.aA.aG.b.b.aG.aA     k.c.aA.aG.b.b.aG.aG                                                                       k.c.aG.a.a.b.a.a                          k.c.aG.a.a.b.a.aA                                                                         k.c.aG.a.a.b.a.aG                                                                         k.c.aG.a.a.b.e.a                                                                          k.c.aG.a.a.b.e.aA                         k.c.aG.a.a.b.e.aG                                                                         k.c.aG.a.a.b.m.a                                                                          k.c.aG.a.a.b.m.aA                                                                         k.c.aG.a.a.b.m.aG                         k.c.aG.a.a.b.ao.a                                                                         k.c.aG.a.a.b.o.aA                                                                         k.c.aG.a.a.b.o.aG                                                                         k.c.aG.a.a.b.E.a                          k.c.aG.a.a.b.E.aA                                                                         k.c.aG.a.a.b.E.aG                                                                         k.c.aG.a.a.b.R.a                                                                          k.c.aG.a.a.b.R.aA                         k.c.aG.a.a.b.R.aG                                                                         k.c.aG.a.a.b.aw.a                                                                         k.c.aG.a.a.b.aw.aA                                    k.c.aG.a.a.b.aw.aG                                                                        k.c.aG.a.amb.aA.a                                                                         k.c.aG.a.a.b.aA.aA                                    k.c.aG.a.a.b.aA.aG                                                                        k.c.aG.a.a.b.aG.a                                                                         k.c.aG.a.a.b.aG.aA                                                                        k.c.aG.a.a.b.aG.aG                        k.c.aG.a.b.a.a.a                                                                          k.c.aG.a.b.a.a.aA                                                                         k.c.aG.a.b.a.a.aG                                                                         k.c.aG.a.b.a.e.a                          k.c.aG.a.b.a.e.aA                                                                         k.c.aG.a.b.a.e.aG                                                                         k.c.aG.a.b.a.m.a                                                                          k.c.aG.a.b.a.m.aA                         k.c.aG.a.b.a.m.aG                                                                         k.c.aG.a.b.a.ao.a                                                                         k.c.aG.a.b.a.o.aA                                                                         k.c.aG.a.b.a.o.aG                         k.c.aG.a.b.a.E.a                                                                          k.c.aG.a.b.a.E.aA                                                                         k.c.aG.a.b.a.E.aG                                                                         k.c.aG.a.b.a.R.a                          k.c.aG.a.b.a.R.aA                                                                         k.c.aG.a.b.a.R.aG                                                                         k.c.aG.a.b.a.aw.a                                     k.c.aG.a.b.a.aw.aA                                                                        k.c.aG.a.b.aJaw.aG                                                                        k.c.aG.a.b.a.aA.a                                     k.c.aG.a.b.a.aA.aA                                                                        k.c.aG.a.b.a.aA.aG                                                                        k.c.aG.a.b.a.aG.a                                     k.c.aG.a.b.a.aG.aA                                                                        k.c.aG.a.b.a.aG.aG                                                                        k.c.aG.a.b.b.a.a                                                                          k.c.aG.a.b.b.a.aA                         k.c.aG.a.b.b.a.aG                                                                         k.c.aG.a.b.b.e.a                                                                          k.c.aG.a.b.b.e.aA                                                                         k.c.aG.a.b.b.e.aG                         k.c.aG.a.b.b.m.a                                                                          k.c.aG.a.b.b.m.aA                                                                         k.c.aG.a.b.b.m.aG                                                                         k.c.aG.a.b.b.ao.a                         k.c.aG.a.b.b.o.aA                                                                         k.c.aG.a.b.b.o.aG                                                                         k.c.aG.a.b.b.E.a                                                                          k.c.aG.a.b.b.E.aA                         k.c.aG.a.b.b.E.aG                                                                         k.c.aG.a.b.b.R.a                                                                          k.c.aG.a.b.b.R.aA                                                                         k.c.aG.a.b.b.R.aG                         k.c.aG.a.b.b.aw.a                                                                         k.c.aG.a.b.b.aw.aA                                                                        k.c.aG.a.b.b.aw.aG                                                                        k.c.aG.a.b.b.aA.a                         k.c.aG.a.b.b.aA.aA                                                                        k.c.aG.a.b.b.aA.aG                                                                        k.c.aG.a.b.b.aG.a                                     k.c.aG.a.b.b.aG.aA                                                                        k.c.aG.a.b.b.aG.aG                                                                        k.c.aG.e.a.b.a.a                                                                          k.c.aG.e.a.b.a.aA                         k.c.aG.e.a.b.a.aG                                                                         k.c.aG.e.a.b.e.a                                                                          k.c.aG.e.a.b.e.aA                                                                         k.c.aG.e.a.b.e.aG                         k.c.aG.e.a.b.m.a                                                                          k.c.aG.e.a.b.m.aA                                                                         k.c.aG.e.a.b.m.aG                                                                         k.c.aG.e.a.b.ao.a                         k.c.aG.e.a.b.o.aA                                                                         k.c.aG.e.a.b.o.aG                                                                         k.c.aG.e.a.b.E.a                                                                          k.c.aG.e.a.b.E.aA                         k.c.aG.e.a.b.F.aG                                                                         k.c.aG.e.a.b.R.a                                                                          k.c.aG.e.a.b.R.aA                                                                         k.c.aG.e.a.b.R.aG                         k.c.aG.e.a.b.aw.a                                                                         k.c.aG.e.a.b.aw.aA                                                                        k.c.aG.e.a.b.aw.aG                                                                        k.c.aG.e.a.b.aA.a                         k.c.aG.e.a.b.aA.aA                                                                        k.c.aG.e.a.b.aA.aG                                                                        k.c.aG.e.a.b.aG.a                                     k.c.aG.e.a.b.aG.aA                                                                        k.c.aG.e.a.b.aG.aG                                                                        k.c.aG.e.b.a.a.a                                                                          k.c.aG.e.b.a.a.aA                         k.c.aG.e.b.a.a.aG                                                                         k.c.aG.e.b.a.e.a                                                                          k.c.aG.e.b.a.e.aA                                                                         k.c.aG.e.b.a.e.aG                         k.c.aG.e.b.a.m.a                                                                          k.c.aG.e.b.a.m.aA                                                                         k.c.aG.e.b.a.m.aG                                                                         k.c.aG.e.b.a.ao.a                         k.c.aG.e.b.a.o.aA                                                                         k.c.aG.e.b.a.o.aG                                                                         k.c.aG.e.b.a.E.a                                                                          k.c.aG.e.b.a.E.aA                         k.c.aG.e.b.a.E.aG                                                                         k.c.aG.e.b.a.R.a                                                                          k.c.aG.e.b.a.R.aA                                                                         k.c.aG.e.b.a.R.aG                         k.c.aG.e.b.a.aw.a                                                                         k.c.aG.e.b.a.aw.aA                                                                        k.c.aG.e.b.a.aw.aG                                                                        k.c.aG.e.b.a.aA.a                         k.c.aG.e.b.a.aA.aA                                                                        k.c.aG.e.b.a.aA.aG                                                                        k.c.aG.e.b.a.aG.a                                     k.c.aG.e.b.a.aG.aA                                                                        k.c.aG.e.b.a.aG.aG                                                                        k.c.aG.e.b.b.a.a                                                                          k.c.aG.e.b.b.a.aA                         k.c.aG.e.b.b.a.aG                                                                         k.c.aG.e.b.b.e.a                                                                          k.c.aG.e.b.b.e.aA                                                                         k.c.aG.e.b.b.e.aG                         k.c.aG.e.b.b.m.a                                                                          k.c.aG.e.b.b.m.aA                                                                         k.c.aG.e.b.b.m.aG                                                                         k.c.aG.e.b.b.ao.a                         k.c.aG.e.b.b.o.aA                                                                         k.c.aG.e.b.b.o.aG                                                                         k.c.aG.e.b.b.E.a                                                                          k.c.aG.e.b.b.E.aA                         k.c.aG.e.b.b.E.aG                                                                         k.c.aG.e.b.b.R.a                                                                          k.c.aG.e.b.b.R.aA                                                                         k.c.aG.e.b.b.R.aG                         k.c.aG.e.b.b.aw.a                                                                         k.c.aG.e.b.b.aw.aA                                                                        k.c.aG.e.b.b.aw.aG                                                                        k.cmaG.e.b.b.aA.a                         k.c.aG.e.b.b.aA.aA                                                                        k.c.aG.e.b.b.aw.aG                                                                        k.c.aG.e.b.b.aG.a                                     k.c.aG.e.b.b.aG.aA                                                                        k.c.aG.e.b.b.aG.aG                                                                        k.c.aG.m.a.b.a.a                                                                          k.c.aG.m.a.b.a.aA                         k.c.aG.m.a.b.a.aG                                                                         k.c.aG.m.a.b.e.a                                                                          k.c.aG.m.a.b.e.aA                                                                         k.c.aG.m.a.b.e.aG                         k.c.aG.m.a.b.m.a                                                                          k.c.aG.m.a.b.m.aA                                                                         k.c.aG.m.a.b.m.aG                                                                         k.c.aG.m.a.b.ao.a                         k.c.aG.m.a.b.o.aA                                                                         k.c.aG.m.a.b.o.aG                                                                         k.c.aG.m.a.b.E.a                                                                          k.c.aG.m.a.b.E.aA                         k.c.aG.m.a.b.E.aG                                                                         k.c.aG.m.a.b.R.a                                                                          k.c.aG.m.a.b.R.aA                                                                         k.c.aG.m.a.b.R.aG                         k.c.aG.m.a.b.aw.a                                                                         k.c.aG.m.a.b.aw.aA                                                k.c.aG.m.a.b.aG.aG                                                                        k.c.aG.m.b.a.a.a                                                                          k.c.aG.m.b.a.a.aA                                                                         k.c.aG.m.b.a.a.aG                         k.c.aG.m.b.a.e.a                                                                          k.c.aG.m.b.a.e.aA                                                                         k.c.aG.m.b.a.e.aG                                                                         k.c.aG.m.b.a.m.a                          k.c.aG.m.b.a.m.aA                                                                         k.c.aG.m.b.a.m.aG                                                                         k.c.aG.m.b.a.ao.a                                                                         k.c.aG.m.b.a.o.aA                         k.c.aG.m.b.a.o.aG                                                                         k.c.aG.m.b.a.E.a                                                                          k.c.aG.m.b.a.E.aA                                                                         k.c.aG.m.b.a.E.aG                         k.c.aG.m.b.a.R.a                                                                          k.c.aG.m.b.a.R.aA                                                                         k.c.aG.m.b.a.R.aG                                                                         k.c.aG.m.b.a.aw.a                         k.c.aG.m.b.a.aw.aA      k.c.aG.m.b.a.aw.aG                                                                        k.c.aG.m.b.a.aA.a                         k.c.a.G.m.b.a.aA.aA     k.c.aG.m.b.a.aA.aG                                                                        k.c.aG.m.b.a.aG.a                         k.c.aG.m.b.a.aG.aA                                                                        k.c.aG.m.b.a.aG.aG                                                                        k.c.aG.m.b.b.a.a                                                                          k.c.aG.m.b.b.a.aA                         k.c.aG.m.b.b.a.aG                                                                         k.c.aG.m.b.b.e.a                                                                          k.c.aG.m.b.b.e.aA                                                                         k.c.aG.m.b.b.e.aG                         k.c.aG.m.b.b.m.a                                                                          k.c.aG.m.b.b.m.aA                                                                         k.c.aG.m.b.b.m.aG                                                                         k.c.aG.m.b.b.ao.a                         k.c.aG.m.b.b.o.aA                                                                         k.c.aG.m.b.b.o.aG                                                                         k.c.aG.m.b.b.E.a                                                                          k.c.aG.m.b.b.E.aA                         k.c.aG.m.b.b.E.aG                                                                         k.c.aG.m.b.b.R.a                                                                          k.c.aG.m.b.b.R.aA                                                                         k.c.aG.m.b.b.R.aG                         k.c.aG.m.b.b.aw.a                                                                         k.c.aG.m.b.b.aw.aA                                                k.c.aG.m.b.b.aw.aG                                                                        k.c.aG.m.b.b.aA.a                                                                         k.c.aG.m.b.b.aA.aA                                    k.c.aG.m.b.b.aA.aG                                                                        k.c.aG.m.b.b.aG.a                                                                         k.c.aG.rh.b.b.aG.aA                                   k.c.aG.m.b.b.aG.aG                                                                        k.c.aG.o.a.b.a.a                                                                          k.c.aG.o.a.b.a.aA                                                                         k.c.aG.o.a.b.a.aG                         k.c.aG.o.a.b.e.a                                                                          k.c.aG.o.a.b.e.aA                                                                         k.c.aG.o.a.b.e.aG                                                                         k.c.aG.o.a.b.m.a                          k.c.aG.o.a.b.m.aA                                                                         k.c.aG.o.a.b.m.aG                                                                         k.c.aG.o.a.b.ao.a                                                                         k.c.aG.o.a.b.o.aA                         k.c.aG.o.a.b.o.aG                                                                         k.c.aG.o.a.b.E.a                                                                          k.c.aG.o.a.b.E.aA                                                                         k.c.aG.o.a.b.E.aG                         k.c.aG.o.a.b.R.a                                                                          k.c.aG.o.a.b.R.aA                                                                         k.c.aG.o.a.b.R.aG                                                                         k.c.aG.o.a.b.aw.a                         k.c.aG.o.a.b.aw.aA                                                                        k.c.amG.o.a.b.a.w.aG                                                                      k.c.aG.o.a.b.aA.a                                     k.c.aG.o.a.b.aA.aA                                                                        k.c.aG.o.a.b.aA.aG                                                                        k.c.aG.o.a.b.aG.a                                     k.c.aG.o.a.b.aG.aA                                                                        k.c.aG.o.a.b.aG.aG                                                                        k.c.aG.o.b.a.a.a                                                                          k.c.aG.o.b.a.a.aA                         k.c.aG.o.b.a.a.aG                                                                         k.c.aG.G.b.a.e.a                                                                          k.c.aG.o.b.a.e.aA                                                                         k.c.aG.o.b.a.e.aG                         k.c.aG.o.b.a.m.a                                                                          k.c.aG.o.b.a.m.aA                                                                         k.c.aG.o.b.a.m.aG                                                                         k.c.aG.o.b.a.ao.a                         k.c.aG.o.b.a.o.aA                                                                         k.c.aG.o.b.a.o.aG                                                                         k.c.a.G.o.b.a.E.a                                                                         k.c.aG.o.b.a.E.aA                         k.c.aG.o.b.a.E.aG                                                                         k.c.aG.o.b.a.R.a                                                                          k.c.aG.o.b.a.R.aA                                                                         k.c.aG.o.b.a.R.aG                         k.c.aG.o.b.a.aw.a                                                                         k.c.aG.o.b.a.aw.aA                                                                        k.c.aG.o.b.a.aw.aG                                                                        k.c.aG.o.b.a.aA.a                         k.c.aG.o.b.a.aA.aA                                                                        k.c.aG.o.b.a.aA.aG                                                                        k.c.aG.o.b.a.aG.a                                     k.c.aG.o.b.a.aG.aA                                                                        k.c.aG.o.b.a.aG.aG                                                                        k.c.aG.o.b.b.a.a                                                                          k.c.aG.o.b.b.a.aA                         k.c.aG.o.b.b.a.aG                                                                         k.c.aG.o.b.b.e.a                                                                          k.c.aG.o.b.b.e.aA.                                                                        k.c.aG.d.b.b.e.aG                         k.c.aG.o.b.b.m.a                                                                          k.c.aG.o.b.b.m.aA                                                                         k.c.aG.o.b.b.m.aG                                                                         k.c.aG.o.b.b.ao.a                         k.c.aG.o.b.b.o.aA                                                                         k.c.aG.o.b.b.o.aG                                                                         k.c.aG.o.b.b.E.a                                                                          k.c.aG.o.b.b.E.aA                         k.c.aG.o.b.b.E.aG                                                                         k.c.aG.o.b.b.R.a                                                                          k.c.aG.o.b.b.R.aA                                                                         k.c.aG.o.b.b.R.aG                         k.c.aG.o.b.b.aw.a                                                                         k.c.aG.o.b.b.aw.aA                                                                        k.c.aG.o.b.b.aw.aG                                                                        k.c.aG.o.b.b.aA.a                         k.c.aG.o.b.b.aA.aA                                                                        k.c.aG.o.b.b.aA.aG                                                                        k.c.aG.o.b.b.aG.a                                     k.c.aG.o.b.b.aG.aA                                                                        k.c.aG.o.b.b.aG.aG                                                                        k.c.aG.E.a.b.a.a                                                                          k.c.aG.E.a.b.a.aA                         k.c.aG.E.a.b.a.aG                                                                         k.c.aG.E.a.b.e.a                                                                          k.c.aG.E.a.b.e.aA                                                                         k.c.aG.E.a.b.e.aG                         k.c.aG.E.a.b.m.a                                                                          k.c.aG.E.a.b.m.aA                                                                         k.c.aG.E.a.b.m.aG                                                                         k.c.aG.E.a.b.ao.a                         k.c.aG.E.a.b.o.aA                                                                         k.c.aG.E.a.b.o.aG                                                                         k.c.aG.E.a.b.E.a                                                                          k.c.aG.E.a.b.E.aA                         k.c.aG.E.a.b.E.aG                                                                         k.c.aG.E.a.b.R.a                                                                          k.c.aG.E.a.b.R.aA                                                                         k.c.aG.E.a.b.R.aG                         k.c.aG.E.a.b.aw.a                                                                         k.c.aG.E.a.b.aw.aA                                                                        k.c.aG.E.a.b.aw.aG                                                                        k.c.aG.E.a.b.aA.a                         k.c.aG.E.a.b.aA.aA                                                                        k.c.aG.E.a.b.aA.aG                                                                        k.c.aG.E.a.b.aG.a                                     k.c.aG.E.a.b.aG.aA                                                                        k.c.aG.E.a.b.aG.aG                                                                        k.c.aG.E.b.a.a.a                                                                          k.c.aG.E.b.a.a.aA                         k.c.aG.E.b.a.a.aG                                                                         k.c.aG.E.b.a.e.a                                                                          k.c.aG.E.b.a.e.aA                                                                         k.c.aG.E.b.a.e.aG                         k.c.aG.E.b.a.m.a                                                                          k.c.aG.E.b.a.m.aA                                                                         k.c.aG.E.b.a.m.aG                                                                         k.c.aG.E.b.a.ao.a                         k.c.aG.E.b.a.o.aA                                                                         k.c.aG.E.b.a.G.aG                                                                         k.c.aG.E.b.a.E.a                                                                          k.c.aG.E.b.a.E                            k.c.aG.E.b.a.E.a.G                                                                        k.c.aG.E.b.a.R.a                                                                          k.c.aG.E.b.a.R.aA                                                                         k.c.aG.E.b.a.R.aG                         k.c.aG.E.b.a.aw.a                                                                         k.c.aG.E.b.a.aw.aA                                                                        k.c.aG.E.b.a.aw.aG                                                                        k.c.aG.E.b.a.aA.a                         k.c.aG.E.b.a.aA.aA                                                                        k.c.aG.E.b.a.aA.aG                                                                        k.c.aG.E.b.a.aG.a                                     k.c.aG.E.b.a.aG.aA                                                                        k.c.aG .b.a.aG.aG                                                                         k.c.aG.E.b.b.a.a                                                                          k.c.aG.E.b.b.a.aA                         k.c.aG.E.b.b.a.aG                                                                         k.c.aG.E.b.b.e.a                                                                          k.c.aG.E.b.b.e.aA                                                                         k.c.aG.E.b.b.e.aG                         k.c.aG.E.b.b.m.a                                                                          k.c.aG.E.b.b.m.aA                                                                         k.c.aG.E.b.b.m.aG                                                                         k.c.aG.E.b.b.ao.a                         k.c.aG.E.b.b.o.aA                                                                         k.c.aG.E.b.b.o.aG                                                                         k.c.aG.E.b.b.E.a                                                                          k.c.aG.E.b.b.E.aA                         k.c.aG.E.b.b.E.aG                                                                         k.c.aG.E.b.b.R.a                                                                          k.c.aG.E.b.b.R.aA                                                                         k.c.aG.E.b.b.R.aG                         k.c.aG.E.b.b.aw.a                                                                         k.c.aG.E.b.b.aw.aA                                                                        k.c.aG.E.b.b.aw.aG                                                                        k.c.aG.E.b.b.aA.a                         k.c.aG.E.b.b.aA.aA                                                                        k.c.aG.E.b.b.aA.aG                                                                        k.c.aG.E.b.b.aG.a                                     k.c.aG.E.b.b.aG.aA                                                                        k.c.aG.E.b.b.aG.aG                                                                        k.c.aG.R.a.b.a.a                                                                          k.c.aG.R.a.b.a.aA                         k.c.aG.R.a.b.a.aG                                                                         k.c.aG.R.a.b.e.a                                                                          k.c.aG.R.a.b.e.aA                                                                         k.c.aG.R.a.b.e.aG                         k.c.aG.R.a.b.m.a                                                                          k.c.aG.R.a.b.m.aA                                                                         k.c.aG.R.a.b.m.aG                                                                         k.c.aG.R.a.b.ao.a                         k.c.aG.R.a.b.o.aA                                                                         k.c.aG.R.a.b.o.aG                                                                         k.c.aG.R.a.b.E.a                                                                          k.c.aG.R.a.b.E.aA                         k.c.aG.R.a.b.E.a.G                                                                        k.c.aG.R.a.b.R.a                                                                          k.c.aG.R.a.b.R.aA                                                                         k.c.aG.R.a.b.R.aG                         k.c.aG.R.a.b.aw.a                                                                         k.c.aG.R.a.b.aw.aA                                                                        k.c.aG.R.a.b.aw.aG                                                                        k.c.aG.R.a.b.aA.a                         k.c.aqR.a.b.aA.aA                                                                         k.c.aG.R.a.b.aA.aG                                                                        k.c.aG.R.a.b.aG.a                                     k.c.aG.R.a.b.aG.aA                                                                        k.c.aG.R.a.b.aG.aG                                                                        k.c.aG.R.b.a.a.a                                                                          k.c.aG.R.b.a.a.aA                         k.c.aG.R.b.a.a.aG                                                                         k.c.aG.R.b.a.e.a                                                                          k.c.aG.R.b.a.e.aA                                                                         k.c.aG.R.b.a.e.aG                         k.c.aG.R.b.a.m.a                                                                          k.c.aG.R.b.a.m.aA                                                                         k.c.aG.R.b.a.m.aG                                                                         k.c.aG.R.b.a.ao.a                         k.c.aG.R.b.a.o.aA                                                                         k.c.aG.R.b.a.o.aG                                                                         k.c.aG.R.b.a.E.a                                                                          k.c.aG.R.b.a.E.aA                         k.c.aG.R.b.a.E.aG                                                                         k.c.aG.R.b.a.R.a                                                                          k.c.aG.R.b.a.R.aA                                                                         k.c.aG.R.b.a.R.aG                         k.c.aG.R.b.a.aw.a                                                                         k.c.aG.R.b.a.aw.aA                                                                        k.c.aG.R.b.a.aw.aG                                                                        k.c.aG.R.b.a.aA.a                         k.c.aG.R.b.a.aA.aA                                                                        k.c.aG.R.b.a.aA.aG                                                                        k.c.aG.R.b.a.aG.a                                     k.c.aG.R.b.a.aG.aA                                                                        k.c.aG.R.b.a.aG.aG                                                                        k.c.aG.R.b.b.a.a                                                                          k.c.aG.R.b.b.a.aA                         k.c.aG.R.b.b.a.aG                                                                         k.c.aG.R.b.b.e.a                                                                          k.c.aG.R.b.b.e.aA                                                                         k.c.aG.R.b.b.e.aG                         k.c.aG.R.b.b.m.a                                                                          k.c.aG.R.b.b.m.aA                                                                         k.c.aG.R.b.b.m.aG                                                                         k.c.aG.R.b.b.ao.a                         k.c.aG.R.b.b.o.aA                                                                         k.c.aG.R.b.b.o.aG                                                                         k.c.aG.R.b.b.E.a                                                                          k.c.aG.R.b.b.E.aA                         k.c.aG.R.b.b.E.aG                                                                         k.c.aG.R.b.b.R.a                                                                          k.c.aG.R.b.b.R.aA                                                                         k.c.aG.R.b.b.R.aG                         k.c.aG.R.b.b.aw.a                                                                         k.c.aG.R.b.b.aw.aA                                                                        k.c.aG.R.b.b.aw.aG                                                                        k.c.aG.R.b.b.aA.a                         k.c.aG.R.b.b.aA.aA                                                                        k.c.aG.R.b.b.aA.aG                                                                        k.c.aG.R.b.b.aG.a                                     k.c.aG.R.b.b.aG.aA                                                                        k.c.aG.R.b.t.aG.aG                                                                        k.c.aG.aw.a.b.a.a                                     k.c.aG.aw.a.b.a.aA                                                                        k.c.aG.aw.a.b.a.aG                                                                        k.c.aG.aw.a.b.e.a                                     k.c.aG.aw.a.b.e.aA                                                                        k.c.aG.aw.a.b.e.aG                                                                        k.c.aG.aw.a.b.m.a                                     k.c.aG.aw.a.b.m.aA      k.c.aG.aw.a.b.m.aG                                                                        k.c.aG.aw.a.b.ao.a                        k.c.aG.aw.a.b.o.aA                                                                        k.c.aG.aw.a.b.o.aG                                                                        k.c.aG.aw.a.b.E.a                                     k.c.aG.aw.a.b.E.aA                                                                        k.c.aG.aw.a.b.E.aG                                                                        k.c.aG.aw.a.b.R.a                                     k.c.aG.aw.a.b.R.aA                                                                        k.c.aG.aw.a.b.R.aG                                                                        k.c.aG.aw.a.b.aw.a                                    k.c.aG.aw.a.b.aw.aA     k.c.aG.aw.a.b.aw.aG                                   k.c.aG.aw.a.b.aA.a                                                                        k.c.aG.aw.a.b.aA.aA                                               k.c.aG.aw.a.b.aA.aG     k.c.aG.aw.a.b.aG.a                                    k.c.aG.aw.a.b.aG.aA     k.c.aG.aw.a.b.aG.aG                                   k.c.aG.aw.h.a.a.a                                                                         k.c.aG.aw.b.a.a.aA                                                                        k.c.aG.aw.b.a.a.aG                                                                        k.c.aG.aw.b.a.e.a                         k.c.aG.aw.b.a.e.aA                                                                        k.c.aG.aw.b.a.e.aG                                                                        k.c.aG.aw.b.a.m.a                                     k.c.aG.aw.b.a.m.aA      k.c.aG.aw.b.a.m.aG                                                                        k.c.aG.aw.b.a.ao.a                        k.c.aG.aw.b.a.o.aA                                                                        k.c.aG.aw.b.a.o.aG                                                                        k.c.aG.aw.b.a.E.a                                     k.c.aG.aw.b.a.E.aA                                                                        k.c.aG.aw.h.a.aG                                                                          k.c.aG.aw.b.a.R.a                                     k.c.aG.aw.b.a.R.aA                                                                        k.c.aG.aw.b.a.R.aG                                                                        k.c.aG.aw.b.a.aw.a                                    k.c.aG.aw.b.a.aw.aA     k.c.aG.aw.b.a.aw.aG                                   k.c.aG.aw.b.a.aA.a                                                                        k.c.aG.aw.b.a.aA.aA                                               k.c.aG.aw.b.a.aA.aG     k.c.aG.aw.b.a.aG.a                                    k.c.aG.aw.b.a.aG.aA     k.c.aG.aw.b.a.aG.aG                                   k.c.aG.aw.b.b.a.a                                                                         k.c.aG.aw.b.b.a.aA                                                                        k.c.aG.aw.b.b.a.aG                                                                        k.c.aG.aw.b.b.e.a                         k.c.aG.aw.b.b.e.aA                                                                        k.c.aG.aw.b.b.e.aG                                                                        k.c.aG.aw.b.b.m.a                                     k.c.aG.aw.b.b.m.aA      k.c.aG.aw.b.b.m.aG                                                                        k.c.aG.aw.b.b.ao.a                        k.c.aG.aw.b.b.o.aA                                                                        k.c.aG.aw.b.b.o.aG                                                                        k.c.aG.aw.b.b.F.a                                     k.c.aG.aw.b.b.E.aA                                                                        k.c.aG.aw.b.b.E.aG                                                                        k.c.aG.aw.b.b.R.a                                     k.c.aG.aw.b.b.R.aA                                                                        k.c.aG.aw.b.b.R.aG                                                                        k.c.aG.aw.b.b.aw.a                                    k.c.aG.aw.b.b.aw.aA     k.c.aG.aw.b.b.aw.aG                                   k.c.aG.aw.b.b.aA.a                                                                        k.c.aG.aw.b.b.aA.aA                                               k.c.aG.aw.b.b.aA.aG     k.c.aG.aw.b.b.aG.a                                    k.c.aG.aw.b.b.aG.aA     k.c.aG.aw.b.b.aG.aG                                   k.c.aG.aA.a.b.a.a                                                                         k.c.aG.aA.a.b.a.aA                                                                        k.c.aG.aA.a.b.a.aG                                                                        k.c.aG.aA.a.b.e.a                         k.c.aG.aA.a.b.e.aA                                                                        k.c.aG.aA.a.b.e.aG                                                                        k.c.aG.aA.a.b.m.a                                     k.c.aG.aA.a.b.m.aA      k.c.aG.aA.a.b.m.aG                                                                        k.c.aG.aA.a.b.ao.a                        k.c.aG.aA.a.b.o.aA                                                                        k.c.aG.aA.a.b.o.aG                                                                        k.c.aG.aA.a.b.E.a                                     k.c.aG.aA.a.b.E.aA                                                                        k.c.aG.aA.a.b.E.aG                                                                        k.c.aG.aA.a.b.R.a                                     k.c.aG.aA.a.b.R.aA                                                                        k.c.aG.aA.a.b.R.aG                                                                        k.c.aG.aA.a.b.aw.a                                    k.c.aG.aA.a.b.aw.aA     k.c.aG.aA.a.b.aw.aG                                   k.c.aG.aA.a.b.aA.a                                                                        k.c.aG.aA.a.b.aA.aA                                               k.c.aG.aA.a.b.aA.aG     k.c.aG.aA.a.b.aG.a                                    k.c.aG.aA.a.b.aG.aA     k.c.aG.aA.a.b.aG.aG                                   k.c.aG.aA.b.a.a.a                                                                         k.c.aG.aA.b.a.a.aA                                                                        k.c.aG.aA.b.a.a.aG                                                                        k.c.aG.aA.b.a.e.a                         k.c.aG.aA.b.a.e.aA                                                                        k.c.aG.aA.b.a.e.aG                                                                        k.c.aG.aA.b.a.m.a                                     k.c.aG.aA.b.a.m.aA      k.c.aG.aA.b.a.m.aG                                                                        k.c.aG.aA.b.a.ao.a                        k.c.aG.aA.b.a.o.aA                                                                        k.c.aG.aA.b.a.o.aG                                                                        k.c.aG.aA.b.a.E.a                                     k.c.aG.aA.b.a.E.aA                                                                        k.c.aG.aA.b.a.E.aG                                                                        k.c.aG.aA.b.a.R.a                                     k.c.aG.aA.b.a.R.aA                                                                        k.c.aG.aA.b.a.R.aG                                                                        k.c.aG.aA.b.a.aw.a                                    k.c.aG.aA.b.a.aw.aA     k.c.aG.aA.b.a.aw.aG                                   k.c.aG.aA.b.a.aA.a                                                                        k.c.aG.aA.b.a.aA.aA                                               k.c.aG.aA.b.a.aA.aG     k.c.aG.aA.b.a.aG.a                                    k.c.aG.aA.b.a.aG.aA     k.c.aG.aA.b.a.aG.aG                                   k.c.aG.aA.b.b.a.a                                                                         k.c.aG.aA.b.b.a.aA                                                                        k.c.aG.aA.b.b.a.aG                                                                        k.c.aG.aA.b.b.e.a                         k.c.aG.aA.b.b.e.aA                                                                        k.c.aG.aA.b.b.e.aG                                                                        k.c.aG.aA.b.b.m.a                                     k.c.aG.aA.b.b.m.aA      k.c.aG.aA.b.b.m.aG                                                                        k.c.aG.aA.b.b.ao.a                        k.c.aG.aA.b.b.o.aA                                                                        k.c.aG.aA.b.b.o.aG                                                                        k.c.aG.aA.b.b.E.a                                     k.c.aG.aA.b.b.E.aA                                                                        k.c.aG.aA.b.b.E.aG                                                                        k.c.aG.aA.b.b.R.a                                     k.c.aG.aA.b.b.R.aA                                                                        k.c.aG.aA.b.b.R.aG                                                                        k.c.aG.aA.b.b.aw.a                                    k.c.aG.aA.b.b.aw.aA     k.c.aG.aA.b.b.aw.aG                                   k.c.aG.aA.b.b.aA.a                                                                        k.c.aG.aA.b.b.aA.aA                                               k.c.aG.aA.b.b.aA.aG     k.c.aG.aA.b.b.aG.a                                    k.c.aG.aA.b.b.aG.aA     k.c.aG.aA.b.b.aG.aG                                   k.c.aG.aG.a.b.a.a                                                                         k.c.aG.aG.a.b.a.aA                                                                        k.c.aG.aG.a.b.a.aG                                                                        k.c.aG.aG.a.b.e.a                         k.c.aG.aG.a.b.e.aA                                                                        k.c.aG.aG.a.b.e.aG                                                                        k.c.aG.aG.a.b.m.a                                     k.c.aG.aG.a.b.m.aA                                                                        k.c.aG.aG.a.b.m.aG                                                                        k.c.aG.aG.a.b.ao.a                                    k.c.aG.aG.a.b.o.aA                                                                        k.c.aG.aG.a.b.o.aG                                                                        k.c.aG.aG.a.b.E.a                                     k.c.aG.aG.a.b.E.aA                                                                        k.c.aG.aG.a.b.E.aG                                                                        k.c.aG.aG.a.b.R.a                                     k.c.aG.aG.a.b.R.aA                                                                        k.c.aG.aG.a.b.R.aG                                                                        k.c.aG.aG.a.b.aw.a                                    k.c.aG.aG.a.b.aw.aA     k.c.aG.aG.a.b.aw.aG                                   k.c.aG.aG.a.b.aA.a                                                                        k.c.aG.aG.a.b.aA.aA                                               k.c.aG.aG.a.b.aA.aG     k.c.aG.aG.a.b.aG.a                                    k.c.aG.aG.a.b.aG.aA     k.c.aG.aG.a.b.aG.aG                                                                       k.c.aG.aG.b.a.a.a                         k.c.aG.aG.b.a.a.aA                                                                        k.c.aG.aG.b.a.a.aG                                                                        k.c.aG.aG.b.a.e.a                                     k.c.aG.aG.b.a.e.aA                                                                        k.c.aG.aG.b.a.e.aG                                                                        k.c.aG.aG.bta.m.a                                     k.c.aG.aG.b.a.m.aA                                                                        k.c.aG.aG.b.a.m.aG                                                                        k.c.aG.aG.b.a.ao.a                                    k.c.aG.aG.b.a.o.aA                                                                        k.c.aG.aG.b.a.o.aG                                                                        k.c.aG.aG.b.a.E.a                                     k.c.aG.aG.b.a.E.aA                                                                        k.c.a.G.aG.b.a.E.aG                                                                       k.c.aG.aG.b.a.R.a                                     k.c.aG.aG.b.a.R.aA                                                                        k.c.aG.aG.b.a.R.aG                                                                        k.c.aG.aG.b.a.aw.a                                    k.c.aG.aG.b.a.aw.aA     k.c.aG.aG.b.a.aw.aG                                   k.c.aG.aG.b.a.aA.a                                                                        k.c.aG.aG.b.a.aA.aA                                               k.c.aG.aG.b.a.aA.aG     k.c.aG.aG.b.a.aG.a                                    k.c.aG.aG.b.a.aG.aA     k.c.aG.aG.b.a.aG.aG                                                                       k.c.aG.aG.b.b.a.a                         k.c.aG.aG.b.b.a.aA                                                                        k.c.aG.aG.b.b.a.aG                                                                        k.c.aG.a.G.b.b.e.a                                    k.c.aG.aG.b.b.e.aA                                                                        k.c.aG.aG.b.b.e.aG                                                                        k.c.aG.aG.b.b.m.a                                     k.c.aG.aG.b.b.m.aA                                                                        k.c.aG.aG.b.b.m.aG                                                                        k.c.aG.aG.b.b.ao.a                                    k.c.aG.aG.b.b.o.aA                                                                        k.c.aG.aG.b.b.o.aG                                                                        k.c.aG.aG.b.b.E.a                                     k.c.aG.aG.b.b.E.aA                                                                        k.c.aG.aG.b.b.E.aG                                                                        k.c.aG.aG.b.b.R.a                                     k.c.aG.aG.b.b.R.aA                                                                        k.c.aG.aG.b.b.R.aG                                                                        k.c.aG.aG.b.b.aw.a                                    k.c.aG.aG.b.b.aw.aA     k.c.aG.aG.b.b.aw.aG                                   k.c.aG.aG.b.b.aA.a                                                                        k.c.aG.aG.b.b.aA.aA                                               k.c.aG.aG.b.b.aA.aG     k.c.aG.aG.b.b.aG.a                                    k.c.aG.aG.b.b.aG.aA     k.c.aG.aG.b.b.aG.aG                                                                       q.c.a.a.a.b.a.a                           q.c.a.a.a.b.a.aA                                                                          q.c.a.a.a.b.a.aG                                                                          q.c.a.a.a.b.e.a                                                                           q.c.a.a.a.b.e.aA                          q.c.a.a.a.b.e.aG                                                                          q.c.a.a.a.b.m.a                                                                           q.c.a.a.a.b.m.aA                                                                          q.c.a.a.a.b.m.aG                          q.c.a.a.a.b.ao.a                                                                          q.c.a.a.a.b.o.aA                                                                          q.c.a.a.a.b.o.aG                                                                          q.c.a.a.a.b.E.a                           q.c.a.a.a.b.E.aA                                                                          q.c.a.a.a.b.E.aG                                                                          q.c.a.a.a.b.R.a                                                                           q.c.a.a.a.b.R.aA                          q.c.a.a.a.b.R.aG                                                                          q.c.a.a.a.b.aw.a                                                                          q.c.a.a.a.b.aw.aA                                                                         q.c.a.a.a.b.aw.aG                         q.c.a.a.a.b.aA.a                                                                          q.c.a.a.a.b.aA.aA                                                                         q.c.a.a.a.b.aA.aG                                                                         q.c.a.a.a.b.aG.a                          q.c.a.a.a.b.aG.aA                                                                         q.c.a.a.a.b.aG.aG                                                                         q.c.a.a.b.a.a.a                                                                           q.c.a.a.b.a.a.aA                          q.c.a.a.b.a.a.aG                                                                          q.c.a.a.b.a.e.a                                                                           q.c.a.a.b.a.e.aA                                                                          q.c.a.a.b.a.e.aG                          q.c.a.a.b.a.m.a                                                                           q.c.a.a.b.a.m.aA                                                                          q.c.a.a.b.a.m.aG                                                                          q.c.a.a.b.a.ao.a                          q.c.a.a.b.a.o.aA                                                                          q.c.a.a.b.a.o.aG                                                                          q.c.a.a.b.a.E.a                                                                           q.c.a.a.b.a.E.aA                          q.c.a.a.b.a.E.aG                                                                          q.c.a.a.b.a.R.a                                                                           q.c.a.a.b.a.R.aA                                                                          q.c.a.a.b.a.R.aG                          q.c.a.a.b.a.aw.a                                                                          q.c.a.a.b.a.aw.a                                                                          q.c.a.a.b.a.aw.aG                                                                         q.c.a.a.b.a.aA.a                          q.c.a.a.b.a.aA.aA                                                                         q.c.a.a.b.a.aA.aG                                                                         q.c.a.a.b.a.aG.a                                                                          q.c.a.a.b.a.aG.aA                         q.c.a.a.b.a.aG.aG                                                                         q.c.a.a.b.b.a.a.                                                                          q.c.a.a.b.b.a.a                                                                           q.c.a.a.b.b.a.aG                          q.c.a.a.b.b.e.a                                                                           q.c.a.a.b.b.e.aA                                                                          q.c.a.a.b.b.e.aG                                                                          q.c.a.a.b.b.m.a                           q.c.a.a.b.b.m.aA                                                                          q.c.a.a.b.b.m.a.G                                                                         q.c.a.a.b.b.ao.a                                                                          q.c.a.a.b.b.o.aA                          q.c.a.a.b.b.o.aG                                                                          q.c.a.a.b.b.E.a                                                                           q.c.a.a.b.b.E.aA                                                                          q.c.a.a.b.b.E.aG                          q.c.a.a.b.b.R.a                                                                           q.c.a.a.b.b.R.aA                                                                          q.c.a.a.b.b.R.aG                                                                          q.c.a.a.b.b.aw.a                          q.c.a.a.b.b.aw.aA                                                                         q.c.a.a.b.b.aw.aG                                                                         q.c.a.a.b.b.aA.a                                                                          q.c.a.a.b.b.aA.aA                         q.c.a.a.b.b.aA.aG                                                                         q.c.a.a.b.b.aG.a                                                                          q.c.a.a.b.b.aG.aA                                                                         q.c.a.a.b.b.aG.aG                         q.c.a.e.a.b.a.a                                                                           q.c.a.e.a.b.a.aA                                                                          q.c.a.e.a.b.a.aG                                                                          q.c.a.e.a.b.e.a                           q.c.a.e.a.b.e.aA                                                                          q.c.a.e.a.b.e.aG                                                                          q.c.a.e.a.b.m.a                                                                           q.c.a.e.a.b.m.aA                          q.c.a.e.a.b.m.aG                                                                          q.c.a.e.a.b.ao.a                                                                          q.c.a.e.a.b.o.aA                                                                          q.c.a.e.a.b.o.aG                          q.c.a.e.a.b.E.a                                                                           q.c.a.e.a.b.E.aA                                                                          q.c.a.e.a.b.E.aG                                                                          q.c.a.e.a.b.R.a                           q.c.a.e.a.b.R.aA                                                                          q.c.a.a.b.R.aG                                                                            q.c.a.e.a.b.aw.a                                                                          q.c.a.e.a.b.aw.aA                         q.c.a.e.a.b.aw.aG                                                                         q.c.a.e.a.b.aA.a                                                                          q.c.a.e.a.b.aA.aA                                                                         q.c.a.e.a.b.aA.aG                         q.c.a.e.a.b.aG.a                                                                          q.c.a.e.a.b.aG.aA                                                                         q.c.a.e.a.b.aG.aG                                                                         q.c.a.e.b.a.a.a                           q.c.a.e.b.a.a.aA                                                                          q.c.a.e.b.a.a.aG                                                                          q.c.a.e.b.a.e.a                                                                           q.c.a.e.b.a.e.aA                          q.c.a.e.b.a.e.aG                                                                          q.c.a.e.b.a.m.a                                                                           q.c.a.e.b.a.m.aA                                                                          q.c.a.e.b.a.m.aG                          q.c.a.e.b.a.ao.a                                                                          q.c.a.e.b.a.o.aA                                                                          q.c.a.e.b.a.o.aG                                                                          q.c.a.e.b.a.E.a                           q.c.a.e.b.a.E.aA                                                                          q.c.a.e.b.a.E.aG                                                                          q.c.a.e.b.a.R.a                                                                           q.c.a.e.b.a.R.aA                          q.c.a.e.b.a.R.aG                                                                          q.c.a.e.b.a.aw.a                                                                          q.c.a.e.b.a.aw.aA                                                                         q.c.a.e.b.a.aw.aG                         q.c.a.e.b.a.aA.a                                                                          q.c.a.e.b.a.aA.aA                                                                         q.c.a.e.b.a.aA.aG                                                                         q.c.a.e.b.a.aG.a                          q.c.a.e.b.a.aG.aA                                                                         q.c.a.e.b.a.aG.aG                                                                         q.c.a.e.b.b.a.a                                                                           q.c.a.e.b.b.a.aA                          q.c.a.e.b.b.a.aG                                                                          q.c.a.e.b.b.e.a                                                                           q.c.a.e.b.b.e.aA                                                                          q.c.a.e.b.b.e.aG                          q.c.a.e.b.b.m.a                                                                           q.c.a.e.b.b.m.aA                                                                          q.c.a.e.b.b.m.aG                                                                          q.c.a.e.b.b.ao.a                          q.c.a.e.b.b.o.aA                                                                          q.c.a.e.b.b.o.aG                                                                          q.c.a.e.b.b.E.a                                                                           q.c.a.e.b.b.E.aA                          q.c.a.e.b.b.E.aG                                                                          q.c.a.e.b.b.R.a                                                                           q.c.a.e.b.b.R.aA                                                                          q.c.a.e.b.b.R.aG                          q.c.a.e.b.b.aw.a                                                                          q.c.a.e.b.b.aw.aA                                                                         q.c.a.e.b.b.aw.aG                                                                         q.c.a.e.b.b.aA.a                          q.c.a.e.b.b.aA.aA                                                                         q.c.a.e.b.b.aA.aG                                                                         q.c.a.e.b.b.aG.a                                                                          q.c.a.e.b.b.aG.aA                         q.c.a.e.b.b.aG.aG                                                                         q.c.a.m.a.b.a.a                                                                           q.c.a.m.a.b.a.aA                                                                          q.c.a.m.a.b.a.aG                          q.c.a.m.a.b.e.a                                                                           q.c.a.m.a.b.e.aA                                                                          q.c.a.m.a.b.e.aG                                                                          q.c.a.m.a.b.m.a                           q.c.a.m.a.b.m.aA                                                                          q.c.a.m.a.b.m.aG                                                                          q.c.a.m.a.b.ao.a                                                                          q.c.a.m.a.b.o.aA                          q.c.a.m.a.b.o.aG                                                                          q.c.a.m.a.b.E.a                                                                           q.c.a.m.a.b.E.aA                                                                          q.c.a.m.a.b.E.aG                          q.c.a.m.a.b.R.a                                                                           q.c.a.m.a.b.R.aA                                                                          q.c.a.m.a.b.R.aG                                                                          q.c.a.m.a.b.aw.a                          q.c.a.m.a.b.aw.aA                                                                         q.c.a.m.a.b.aw.aG                                                                         q.c.a.m.a.b.aA.a                                                                          q.c.a.m.a.b.aA.aA                         q.c.a.m.a.b.aA.aG                                                                         q.c.a.m.a.b.aG.a                                                                          q.c.a.m.a.b.aG.aA                                                                         q.c.a.m.a.b.aG.aG                         q.c.a.m.b.a.a.a                                                                           q.c.a.m.b.a.a.aA                                                                          q.c.a.m.b.a.a.aG                                                                          q.c.a.m.b.a.e.a                           q.c.a.m.b.a.e.aA                                                                          q.c.a.m.b.a.e.aG                                                                          q.c.a.m.b.a.m.a                                                                           q.c.a.m.b.a.m.aA                          q.c.a.m.b.a.m.aG                                                                          q.c.a.m.b.a.ao.a                                                                          q.c.a.m.b.a.o.a.A                                                                         q.c.a.m.b.a.o.aG                          q.c.a.m.b.a.E.a                                                                           q.c.a.m.b.a.E.aA                                                                          q.c.a.m.b.a.E.aG                                                                          q.c.a.m.b.a.R.a                           q.c.a.m.b.a.R.aA                                                                          q.c.a.m.b.a.R.aG                                                                          q.c.a.m.b.a.aw.a                                                                          q.c.a.m.b.a.aw.aA                         q.c.a.m.b.a.aw.aG                                                                         q.c.a.m.b.a.aA.a                                                                          q.c.a.m.b.a.aA.aA                                                                         q.c.a.m.b.a.aA.aG                         q.c.a.m.b.a.aG.a                                                                          q.c.a.m.b.a.aG.aA                                                                         q.c.atm.b.a.aG.aG                                                                         q.c.a.m.b.b.a.a                           q.c.a.m.b.b.a.aA                                                                          q.c.a.m.b.b.a.aG                                                                          q.c.a.m.b.b.e.a                                                                           q.c.a.m.b.b.e.aA                          q.c.a.m.b.b.e.aG                                                                          q.c.a.m.b.b.m.a                                                                           q.c.a.m.b.b.m.aA                                                                          q.c.a.m.b.b.m.aG                          q.c.a.m.b.b.ao.a                                                                          q.c.a.m.b.b.o.aA                                                                          q.c.a.m.b.b.o.aG                                                                          q.c.a.m.b.b.E.a                           q.c.a.m.b.b.E.aA                                                                          q.c.a.m.b.b.E.aG                                                                          q.c.a.m.b.b.R.a                                                                           q.c.a.m.b.b.R.aA                          q.c.a.m.b.b.R.aG                                                                          q.c.a.m.b.b.aw.a                                                                          q.c.a.m.b.b.aw.aA                                                                         q.c.a.m.b.b.aw.aG                         q.c.a.m.b.b.aA.a                                                                          q.c.a.m.b.b.aA.aA                                                                         q.c.a.m.b.b.aA aG                                                                         q.c.a.m.b.b.aG.a                          q.c.a.m.b.aG.aA                                                                           q.c.a.m.b.b.aG.aG                                                                         q.c.a.o.a.b.a.a                                                                           q c.a.o.a.b.a.aA                          q.c.a.o.a.b.a.aG                                                                          q.c.a.o.a.b.e.a                                                                           q.c.a.o.a.b.e.aA                                                                          q c.a.o.a.b.e.aG                          q.c.a.o.a.b.m.a                                                                           q.c.a.o.a.b.m.aA                                                                          q.c.a.o.a.b.m.aG                                                                          q.c.a.o.a.b.ao.a                          q.c.a.o.a.b.o.aA                                                                          q.c.a.o.a.b.o.aG                                                                          q.c.a.o.a.b.E.a                                                                           q.c.a.o.a.b.E.aA                          q.c.a.o.a.b.E.aG                                                                          q.c.a.o.a.b.R.a                                                                           q.c.a.o.a.b.R.aA                                                                          q.c.a.o.a.b.R.aG                          q.c.a.o.a.b.aw.a                                                                          q.c.a.o.a.b.aw.aA                                                                         q.c.a.o.a.b.aw.aG                                                                         q.c.a.o.a.b.aA.a                          q.c.a.o.a.b.aA.aA                                                                         q.c.a.d.a.b.aA.aG                                                                         q.c.a.o.a.b.aG.a                                                                          q.c.a.o.a.b.aG.aA                         q.c.a.o.a.b.aG.aG                                                                         q.c.a.o.b.a.a.a                                                                           q.c.a.o.b.a.a.aN                                                                          q.c.a.o.b.a.a.aG                          q.c.a.o.b.a.e.a                                                                           q.c.a.o.b.a.e.aA                                                                          q.c.a.o.b.a.e.aG                                                                          q.c.a.o.b.a.m.a                           q.c.a.o.b.a.m.aA                                                                          q.c.a.o.b.a.m.aG                                                                          q.c.a.o.b.a.ao.a                                                                          q.c.a.o.b.a.o.aA                          q.c.a.o.b.a.o.aG                                                                          q.c.a.o.b.a.E.a                                                                           q.c.a.d.b.a.E.aA                                                                          q.c.a.o.b.a.E.a.G                         q.c.a.o.b.a.R.a                                                                           q.c.a.o.b.a.R.aA                                                                          q.c.a.o.b.a.R.aG                                                                          q.c.a.o.b.a.aw.a                          q.c.a.p.b.a.aw.aA                                                                         q.c.a.o.b.a.aw.aG                                                                         q.c.a.d.b.a.aA.a                                                                          q.c.a.o.b.a.aA.aA                         q.c.a.o.b.a.aA.aG                                                                         q.c.a.o.b.a.aG.a                                                                          q.c.a.o.b.a.aG.aA                                                                         q.c.a.o.b.a.aG.aG                         q.c.a.o.b.b.a.a                                                                           q.c.a.o.b.b.a.aA                                                                          q.c.a.o.b.b.a.aG                                                                          q.c.a.o.b.b.e.a                           q.c.a.o.b.b.e.aA                                                                          q.c.a.o.b.b.e.aG                                                                          q.c.a.o.b.b.m.a                                                                           q.c.a.o.b.b.m.aA                          q.c.a.o.b.b.m.aG                                                                          q.c.a.o.b.b.ao.a                                                                          q.c.a.o.b.b.o.aA                                                                          q.c.a.o.b.b.o.aG                          q.c.a.o.b.b.E.a                                                                           q.c.a.o.b.b.E.aA                                                                          q.c.a.o.b.b.E.aG                                                                          q.c.a.o.b.b.R.a                           q.c.a.o.b.b.R.aA                                                                          q.c.a.o.b.b.R.aG                                                                          q.c.a.o.b.b.aw.a                                                                          q.c.a.o.b.b.aw.aA                         q.c.a.o.b.b.aw.aG                                                                         q.c.a.o.b.b.aA.a                                                                          q.c.a.o.b.b.aA.aA                                                                         q.c.a.o.b.b.aA.aG                         q.c.a.o.b.b.aG.a                                                                          q.c.a.o.b.b.aG.aA                                                                         q.c.a.o.b.b.aG.aG                                                                         q.c.a.E.a.b.a.a                           q.c.a.E.a.b.a.aA                                                                          q.c.a.E.a.b.a.aG                                                                          q.c.a.E.a.b.e.a                                                                           q.c.a.E.a.b.e.aA                          q.c.a.E.a.b.e.aG                                                                          q.c.a.E.a.b.m.a                                                                           q.c.a.E.a.b.m.aA                                                                          q.c.a.E.a.b.m.aG                          q.c.a.E.a.b.ao.a                                                                          q.c.a.E.a.b.o.aA                                                                          q.c.a.E.a.b.o.aG                                                                          q.c.a.E.a.b.E.a                           q.c.a.E.a.b.E.aA                                                                          q.c.a.E.a.b.E.aG                                                                          q.c.a.E.a.b.R.a                                                                           q.c.a.E.a.b.R.aA                          q.c.a.E.a.b.R.aG                                                                          q.c.a.E.a.b.aw.a                                                                          q.c.a.E.a.b.aw.aA                                                                         q.c.a.E.a.b.aw.aG                         q.c.a.E.a.b.a.A.a                                                                         q.c.a.E.a.b.aA.aA                                                                         q.c.a.E.a.b.aA.aG                                                                         q.c.a.E.a.b.aG.a                          q.c.a.E.a.b.aG.aA                                                                         q.c.a.E.a.b.aG.aG                                                                         q.c.a.E.h.a.a.a                                                                           q.c.a.E.b.a.a.aA                          q.c.a.E.b.a.a.aG                                                                          q.c.a.b.a.e.a                                                                             q.c.a.E.b.a.e.aA                                                                          q.c.a.E.b.a.e.aG                          q.c.a.E.b.a.m.a                                                                           q.c.a.E.b.a.m.aA                                                                          q.c.a.E.b.a.m.aG                                                                          q.c.a.E.b.a.ao.a                          q.c.a.E.b.a.o.aA                                                                          q.c.a.E.b.a.o.aG                                                                          q.c.a.E.b.a.E.a                                                                           q.c.a.E.b.a.E.aA                          q.c.a.E.b.a.E.aG                                                                          q.c.a.E.b.a.R.a                                                                           q.c.a.E.b.a.R.aA                                                                          q.c.a.E.b.a.R.aG                          q.c.a.E.b.a.aw.a                                                                          q.c.a.E.b.a.aw.aA                                                                         q.c.a.E.b.a.aw.aG                                                                         q.c.a.E.b.a.R.a                           q.c.a.E.b.a.aA.aA                                                                         q.c.a.E.b.a.aA.aG                                                                         q.c.a.E.b.a.aG.a                                                                          q.c.a.E.b.a.aG.aA                         q.c.a.E.b.a.aG.aG                                                                         q.c.a.E.b.b.a.a                                                                           q.c.a.E.b.b.a.aA                                                                          q.c.a.E.b.b.a.aG                          q.c.a.E.b.b.e.a                                                                           q.c.a.E.b.b.e.aA                                                                          q.c.a.E.b.b.e.aG                                                                          q.c.a.E.b.b.m.a                           q.c.a.E.b.b.m.aA                                                                          q.c.a.E.b.b.m.aG                                                                          q.c.a.E.b.b.ao.a                                                                          q.c.a.E.b.b.o.aA                          q.c.a.E.b.b.o.aG                                                                          q.c.a.E.b.b.E.a                                                                           q.c.a.E.b.b.E.aA                                                                          q.c.a.E.b.b.E.aG                          q.c.a.E.b.b.R.a                                                                           q.c.a.E.b.b.R.aA                                                                          q.c.a.E.b.b.R.aG                                                                          q.c.a.E.b.b.aw.a                          q.c.a.E.b.b.aw.aA                                                                         q.c.a.E.b.b.aw.aG                                                                         q.c.a.E.b.b.aA.a                                                                          q.c.a.E.b.b.aA.aA                         q.c.a.E.b.b.aA.aG                                                                         q.c.a.E.b.b.aG.a                                                                          q.c.a.E.b.b.aG.aA                                                                         q.c.a.E.b.b.aG.aG                         q.c.a.R.a.b.a.a                                                                           q.c.a.R.a.b.a.aA                                                                          q.c.a.R.a.b.a.aG                                                                          q.c.a.R.a.b.e.a                           q.c.a.R.a.b.e.aA                                                                          q.c.a.R.a.b.e.aG                                                                          q.c.a.R.a.b.m.a                                                                           q.c.a.R.a.b.m.aA                          q.c.a.R.a.b.m.aG                                                                          q.c.a.R.a.b.ao.a                                                                          q.c.a.R.a.b.o.aA                                                                          q.c.a.R.a.b.o.aG                          q.c.a.R.a.b.E.a                                                                           q.c.a.R.a.b.E.aA                                                                          q.c.a.R.a.b.E.aG                                                                          q.c.a.R.a.b.R.a                           q.c.a.R.a.b.R.aA                                                                          q.c.a.R.a.b.R.aG                                                                          q.c.a.R.a.b.aw.a                                                                          q.c.a.R.a.b.aw.aA                         q.c.a.R.a.b.aw.aG                                                                         q.c.a.R.a.b.aA.a                                                                          q.c.a.R.a.b.aA.aA                                                                         q.c.a.R.a.b.aA.aG                         q.c.a.R.a.b.aG.a                                                                          q.c.a.R.a.b.aG.aA                                                                         q.c.a.R.a.b.aG.aG                                                                         q.c.a.R.b.a.a.a                           q.c.a.R.b.a.a.aA                                                                          q.c.a.R.b.a.a.aG                                                                          q.c.a.R.b.a.e.a                                                                           q.c.a.R.b.a.e.aA                          q.c.a.R.b.a.e.aG                                                                          q.c.a.R.b.a.m.a                                                                           q.c.a.R.b.a.m.aA                                                                          q.c.a.R.b.a.m.aG                          q.c.a.R.b.a.ao.a                                                                          q.c.a.R.b.a.o.aA                                                                          q.c.a.R.b.a.o.aG                                                                          q.c.a.R.b.a.E.a                           q.c.a.R.b.a.E.aA                                                                          q.c.a.R.b.a.E.aG                                                                          q.c.a.R.b.a.R.a                                                                           q.c.a.R.b.a.R.aA                          q.c.a.R.b.a.R.aG                                                                          q.c.a.R.b.a.aw.a                                                                          q.c.a.R.b.a.aw.aA                                                                         q.c.a.R.b.a.aw.aG                         q.c.a.R.b.a.aA.a                                                                          q.c.a.R.b.a.aA.aA                                                                         q.c.a.R.b.a.aA.aG                                                                         q.c.a.R.b.a.aG.a                          q.c.a.R.b.a.aG.aA                                                                         q.c.a.R.b.a.aG.aG                                                                         q.c.a.R.b.b.a.a                                                                           q.c.a.R.b.b.a.aA                          q.c.a.R.b.b.a.aG                                                                          q.c.a.R.b.b.e.a                                                                           q.c.a.R.b.b.e.aA                                                                          q.c.a.R.b.b.e.aG                          q.c.a.R.b.b.m.a                                                                           q.c.a.R.b.b.m.aA                                                                          q.c.a.R.b.b.m.aG                                                                          q.c.a.R.b.b.ao.a                          q.c.a.R.b.b.o.aA                                                                          q.c.a.R.b.b.o.aG                                                                          q.c.a.R.b.b.E.a                                                                           q.c.a.R.b.b.E.aA                          q.c.a.R.b.b.E.aG                                                                          q.c.a.R.b.b.R.a                                                                           q.c.a.R.b.b.R.aA                                                                          q.c.a.R.b.b.R.aG                          q.c.a.R.b.b.aw.a                                                                          q.c.a.R.b.b.aw.aA                                                                         q.c.a.R.b.b.aw.aG                                                                         q.c.a.R.b.b.aA.a                          q.c.a.R.b.b.aA.aA                                                                         q.c.a.R.b.b.aA.aG                                                                         q.c.a.R.b.b.aG.a                                                                          q.c.a.R.b.b.aG.aA                         q.c.a.R.b.b.aG.aG                                                                         q.c.a.aw.a.b.a.a                                                                          q.c.a.aw.a.b.a.aA                                                                         q.c.a.aw.a.b.a.aG                         q.c.a.aw.a.b.e.a                                                                          q.c.a.aw.a.b.e.aA                                                                         q.c.a.aw.a.b.e.aG                                                                         q.c.a.aw.a.b.m.a                          q.c.a.aw.a.b.m.aA                                                                         q.c.a.aw.a.b.m.aG                                                                         q.c.a.aw.a.b.ao.a                                                                         q.c.a.aw.a.b.o.aA                         q.c.a.aw.a.b.o.aG                                                                         q.c.a.aw.a.b.E.a                                                                          q.c.a.aw.a.b.E.aA                                                                         q.c.a.aw.a.b.E.aG                         q.c.a.aw.a.b.R.a                                                                          q.c.a.aw.a.b.R.aA                                                                         q.c.a.aw.a.b.R.aG                                                                         q.c.a.aw.a.b.aw.a                         q.c.a.aw.a.b.aw.aA                                                                        q.c.a.aw.a.b.aw.aG                                                                        q.c.a.aw.a.b.aA.a                                     q.c.a.aw.a.b.aA.aA                                                                        q.c.a.aw.a.b.aA.aG                                                                        q.c.a.aw.a.b.aG.a                                     q.c.a.aw.a.b.aG.aA                                                                        q.c.a.aw.a.b.aG.aG                                                                        q.c.a.aw.b.a.a.a                                                                          q.c.a.aw.b.a.a.aA                         q.c.a.aw.b.a.a.aG                                                                         q.c.a.aw.b.a.e.a                                                                          q.c.a.aw.b.a.e.aA                                                                         q.c.a.aw.b.a.e.aG                         q.c.a.aw.b.a.m.a                                                                          q.c.a.aw.b.a.m.aA                                                                         q.c.a.aw.b.a.m.aG                                                                         q.c.a.aw.b.a.ao.a                         q.c.a.aw.b.a.o.aA                                                                         q.c.a.aw.b.a.o.aG                                                                         q.c.a.aw.b.a.E.a                                                                          q.c.a.aw.b.a.E.aA                         q.c.a.aw.b.a.E.aG                                                                         q.c.a.aw.b.a.R.a                                                                          q.c.a.aw.b.a.R.aA                                                                         q.c.a.aw.b.a.R.aG                         q.c.a.aw.b.a.aw.a                                                                         q.c.a.aw.b.a.aw.aA                                                                        q.c.a.aw.b.a.aw.aG                                                                        q.c.a.aw.b.a.aA.a                         q.c.a.aw.b.a.aA.aA                                                                        q.c.a.aw.b.a.aA.aG                                                                        q.c.a.aw.b.a.aG.a                                     q.c.a.aw.b.a.aG.aA                                                                        q.c.a.aw.b.a.aG.aG                                                                        q.c.a.aw.b.b.a.a                                                                          q.c.a.aw.b.b.a.aA                         q.c.a.aw.b.b.a.aG                                                                         q.c.a.aw.b.b.e.a                                                                          q.c.a.aw.b.b.e.aA                                                                         q.c.a.aw.b.b.e.aG                         q.c.a.aw.b.b.m.a                                                                          q.c.a.aw.b.b.m.aA                                                                         q.c.a.aw.b.b.m.aG                                                                         q.c.a.aw.b.b.ao.a                         q.c.a.aw.b.b.o.aA                                                                         q.c.a.aw.b.b.o.aG                                                                         q.c.a.aw.b.b.E.a                                                                          q.c.a.aw.b.b.E.aA                         q.c.a.aw.b.b.E.aG                                                                         q.c.a.aw.b.b.R.a                                                                          q.c.a.aw.b.b.R.aA                                                                         q.c.a.aw.b.b.R.aG                         q.c.a.aw.b.b.aw.a                                                                         q.c.a.aw.b.b.aw.aA                                                                        q.c.a.aw.b.b.aw.aG                                                                        q.c.a.aw.b.b.aA.a                         q.c.a.aw.b.b.aA.aA                                                                        q.c.a.aw.b.b.aA.aG                                                                        q.c.a.aw.b.b.aG.a                                     q.c.a.aw.b.b.aG.aA                                                                        q.c.a.aw.b.b.aG.aG                                                                        q.c.a.aA.a.b.a.a                                                                          q.c.a.aA.a.b.a.aA                         q.c.a.aA.a.b.a.aG                                                                         q.c.a.aA.a.b.e.a                                                                          q.c.a.aA.a.b.e.aA                                                                         q.c.a.aA.a.b.e.aG                         q.c.a.aA.a.b.m.a                                                                          q.c.a.aA.a.b.m.aA                                                                         q.c.a.aA.a.b.m.aG                                                                         q.c.a.aA.a.b.ao.a                         q.c.a.aA.a.b.o.aA                                                                         q.c.a.aA.a.b.o.aG                                                                         q.c.a.aA.a.b.E.a                                                                          q.c.a.aA.a.b.E.aA                         q.c.a.aA.a.b.E.aG                                                                         q.c.a.aA.a.b.R.a                                                                          q.c.a.aA.a.b.R.aA                                                                         q.c.a.aA.a.b.R.aG                         q.c.a.aA.a.b.aw.a                                                                         q.c.a.aA.a.b.aw.aA                                                                        q.c.a.aA.a.b.aw.aG                                                                        q.c.a.aA.a.b.aA.a                         q.c.a.aA.a.b.aA.aA                                                                        q.c.a.aA.a.b.aA.aG                                                                        q.c.a.aA.a.b.aG.a                                     q.c.a.aA.a.b.aG.aA                                                                        q.c.a.aA.a.b.aG.aG                                                                        q.c.a.aA.b.a.a.a                                                                          q.c.a.aA.b.a.a.aA                         q.c.a.aA.b.a.a.aG                                                                         q.c.a.aA.b.a.e.a                                                                          q.c.a.aA.b.a.e.aA                                                                         q.c.a.aA.b.a.e.aG                         q.c.a.aA.b.a.m.a                                                                          q.c.a.aA.b.a.m.aA                                                                         q.c.a.aA.b.a.m.aG                                                                         q.c.a.aA.b.a.ao.a                         q.c.a.aA.b.a.o.aA                                                                         q.c.a.aA.b.a.o.aG                                                                         q.c.a.aA.b.a.E.a                                                                          q.c.a.aA.b.a.E.aA                         q.c.a.aA.b.a.E.aG                                                                         q.c.a.aA.b.a.R.a                                                                          q.c.a.aA.b.a.R.aA                                                                         q.c.a.aA.b.a.R.aG                         q.c.a.aA.b.a.aw.a                                                                         q.c.a.aA.b.a.aw.aA                                                                        q.c.a.aA.b.a.aw.aG                                                                        q.c.a.aA.b.a.aA.a                         q.c.a.aA.b.a.aA.aA                                                                        q.c.a.aA.b.a.aA.aG                                                                        q.c.a.aA.b.a.aG.a                                     q.c.a.aA.b.a.aG.aA                                                                        q.c.a.aA.b.a.aG.aG                                                                        q.c.a.aA.b.b.a.a                                                                          q.c.a.aA.b.b.a.aA                         q.c.a.aA.b.b.a.aG                                                                         q.c.a.aA.b.b.e.a                                                                          q.c.a.aA.b.b.e.aA                                                                         q.c.a.aA.b.b.e.aG                         q.c.a.aA.b.b.m.a                                                                          q.c.a.aA.b.b.m.aA                                                                         q.c.a.aA.b.b.m.aG                                                                         q.c.a.aA.b.b.ao.a                         q.c.a.aA.b.b.o.aA                                                                         q.c.a.aA.b.b.o.aG                                                                         q.c.a.aA.b.b.E.a                                                                          q.c.a.aA.b.b.E.aA                         q.c.a.aA.b.b.E.aG                                                                         q.c.a.aA.b.b.R.a                                                                          q.c.a.aA.b.b.R.aA                                                                         q.c.a.aA.b.b.R.aG                         q.c.a.aA.b.b.aw.a                                                                         q.c.a.aA.b.b.aw.aA                                                                        q.c.a.aA.b.b.aw.aG                                                                        q.c.a.aA.b.b.aA.a                         q.c.a.aA.b.b.aA.aA                                                                        q.c.a.aA.b.b.aA.aG                                                                        q.c.a.aA.b.b.aG.a                                     q.c.a.aA.b.b.aG.aA                                                                        q.c.a.aA.b.b.aG.aG                                                q.c.a.aG.a.b.a.a                                                                          q.c.a.aG.a.b.a.aA                                                                         q.c.a.aG.a.b.a.aG                                                                         q.c.a.aG.a.b.e.a                          q.c.a.aG.a.b.e.aA                                                                         q.c.a.aG.a.b.e.aG                                                                         q.c.a.aG.a.b.m.a                                                                          q.c.a.aG.a.b.m.aA                         q.c.a.aG.a.b.m.aG                                                                         q.c.a.aG.a.b.ao.a                                                                         q.c.a.aG.a.b.o.aA                                                                         q.c.a.aG.a.b.o.aG                         q.c.a.aG.a.b.E.a                                                                          q.c.a.aG.a.b.E.aA                                                                         q.c.a.aG.a.b.E.aG                                                                         q.c.a.aG.a.b.R.a                          q.c.a.aG.a.b.R.aA                                                                         q.c.a.aG.a.b.R.aG                                                                         q.c.a.aG.a.b.aw.a                                     q.c.a.aG.a.b.aw.aA                                                                        q.c.a.aG.a.b.aw.aG                                                                        q.c.a.aG.a.b.aA.a                                     q.c.a.aG.a.b.aA.aA                                                                        q.c.a.aG.a.b.aA.aG                                                                        q.c.a.aG.a.b.aG.a                                                                         q.c.a.aG.a.b.aG.aA                        q.c.a.aG.a.b.aG.aG                                                                        q.c.a.aG.b.a.a.a                                                                          q.c.a.aG.b.a.a.aA                                                                         q.c.a.aG.b.a.a.aG                         q.c.a.aG.b.a.e.a                                                                          q.c.a.aG.b.a.e.aA                                                                         q.c.a.aG.b.a.e.aG                                                                         q.c.a.aG.b.a.m.a                          q.c.a.aG.b.a.m.aA                                                                         q.c.a.aG.b.a.m.aG                                                                         q.c.a.aG.b.a.ao.a                                                                         q.c.a.aG.b.a.o.aA                         q.c.a.aG.b.a.o.aG                                                                         q.c.a.aG.b.a.E.a                                                                          q.c.a.aG.b.a.E.aA                                                                         q.c.a.aG.b.a.E.aG                         q.c.a.aG.b.a.R.a                                                                          q.c.a.aG.b.a.R.aA                                                                         q.c.a.aG.b.a.R.aG                                                                         q.c.a.aG.b.a.aw.a                         q.c.a.aG.b.a.aw.aA                                                                        q.c.a.aG.b.a.aw.aG                                                                        q.c.a.aG.b.a.aA.a                                     q.c.a.aG.b.a.aA.aA                                                                        q.c.a.aG.b.a.aA.aG                                                                        q.c.a.aG.b.a.aG.a                                                                         q.c.a.aG.b.a.aG.aA                        q.c.a.aG.b.a.aG.aG                                                                        q.c.a.aG.b.b.a.a                                                                          q.c.a.aG.b.b.a.aA                                                                         q.c.a.aG.b.b.a.aG                         q.c.a.aG.b.b.e.a                                                                          q.c.a.aG.b.b.e.aA                                                                         q.c.a.aG.b.b.e.aG                                                                         q.c.a.aG.b.b.m.a                          q.c.a.aG.b.b.m.aA                                                                         q.c.a.aG.b.b.m.aG                                                                         q.c.a.aG.b.b.ao.a                                                                         q.c.a.aG.b.b.o.aA                         q.c.a.aG.b.b.o.aG                                                                         q.c.a.aG.b.b.E.a                                                                          q.c.a.aG.b.b.E.aA                                                                         q.c.a.aG.b.b.E.aG                         q.c.a.aG.b.b.R.a                                                                          q.c.a.aG.b.b.R.aA                                                                         q.c.a.aG.b.b.R.aG                                                                         q.c.a.aG.b.b.aw.a                         q.c.a.aG.b.b.aw.aA                                                                        q.c.a.aG.b.b.aw.aG                                                                        q.c.a.aG.b.b.aA.a                                     q.c.a.aG.b.b.aA.aA                                                                        q.c.a.aG.b.b.aA.aG                                                                        q.c.a.aG.b.b.aG.a                                                                         q.c.a.aG.b.b.aG.aA                        q.c.a.aG.b.b.aG.aG                                                                        q.c.aA.a.a.b.a.a                                                                          q.c.aA.a.a.b.a.aA                                                                         q.c.aA.a.a.b.a.aG                         q.c.aA.a.a.b.e.a                                                                          q.c.aA.a.a.b.e.aA                                                                         q.c.aA.a.a.b.e.aG                                                                         q.c.aA.a.a.b.m.a                          q.c.aA.a.a.b.m.aA                                                                         q.c.aA.a.a.b.m.aG                                                                         q.c.aA.a.a.b.ao.a                                                                         q.c.aA.a.a.b.o.aA                         q.c.aA.a.a.b.o.aG                                                                         q.c.aA.a.a.b.E.a                                                                          q.c.aA.a.a.b.E.aA                                                                         q.c.aA.a.a.b.E.aG                         q.c.aA.a.a.b.R.a                                                                          q.c.aA.a.a.b.R.aA                                                                         q.c.aA.a.a.b.R.aG                                                                         q.c.aA.a.a.b.aw.a                         q.c.aA.a.a.b.aw.aA                                                                        q.c.aA.a.a.b.aw.aG                                                                        q.c.aA.a.a.b.aA.a                                     q.c.aA.a.a.b.aA.aA                                                                        q.c.aA.a.a.b.aA.aG                                                                        q.c.aA.a.a.b.aG.a                                     q.c.aA.a.a.b.aG.aA                                                                        q.c.aA.a.a.b.aG.aG                                                                        q.c.aA.a.b.a.a.a                                                                          q.c.aA.a.b.a.a.aA                         q.c.aA.a.b.a.a.aG                                                                         q.c.aA.a.b.a.e.a                                                                          q.c.aA.a.b.a.e.aA                                                                         q.c.aA.a.b.a.e.aG                         q.c.aA.a.b.a.m.a                                                                          q.c.aA.a.b.a.m.aA                                                                         q.c.aA.a.b.a.m.aG                                                                         q.c.aA.a.b.a.ao.a                         q.c.aA.a.b.a.o.aA                                                                         q.c.aA.a.b.a.o.aG                                                                         q.c.aA.a.b.a.E.a                                                                          q.c.aA.a.b.a.E.aA                         q.c.aA.a.b.a.E.aG                                                                         q.c.aA.a.b.a.R.a                                                                          q.c.aA.a.b.a.R.aA                                                                         q.c.aA.a.b.a.R.aG                         q.c.aA.a.b.a.aw.a                                                                         q.c.aA.a.b.a.aw.aA                                                                        q.c.aA.a.b.a.aw.aG                                                                        q.c.aA.a.b.a.aA.a                         q.c.aA.a.b.a.aA.aA                                                                        q.c.aA.a.b.a.aA.aG                                                                        q.c.aA.a.b.a.aG.a                                     q.c.aA.a.b.a.aG.aA                                                                        q.c.aA.a.b.a.aG.aG                                                                        q.c.aA.a.b.b.a.a                                                                          q.c.aA.a.b.b.a.aA                         q.c.aA.a.b.b.a.aG                                                                         q.c.aA.a.b.b.e.a                                                                          q.c.aA.a.b.b.e.aA                                                                         q.c.aA.a.b.b.e.aG                         q.c.aA.a.b.b.m.a                                                                          q.c.aA.a.b.b.m.aA                                                                         q.c.aA.a.b.b.m.aG                                                                         q.c.aA.a.b.b.ao.a                         q.c.aA.a.b.b.o.aA                                                                         q.c.aA.a.b.b.o.aG                                                                         q.c.aA.a.b.b.E.a                                                                          q.c.aA.a.b.b.E.aA                         q.c.aA.a.b.b.E.aG                                                                         q.c.aA.a.b.b.R.a                                                                          q.c.aA.a.b.b.R.aA                                                                         q.c.aA.a.b.b.R.aG                         q.c.aA.a.b.b.aw.a                                                                         q.c.aA.a.b.b.aw.aA                                                                        q.c.aA.a.b.b.aw.aG                                                                        q.c.aA.a.b.b.aA.a                         q.c.aA.a.b.b.aA.aA                                                                        q.c.aA.a.b.b.aA.aG                                                                        q.c.aA.a.b.b.aG.a                                     q.c.aA.a.b.b.aG.aA                                                                        q.c.aA.a.b.b.aG.aG                                                                        q.c.aA.e.a.b.a.a                                                                          q.c.aA.e.a.b.a.aA                         q.c.aA.e.a.b.a.aG                                                                         q.c.aA.e.a.b.e.a                                                                          q.c.aA.e.a.b.e.aA                                                                         q.c.aA.e.a.b.e.aG                         q.c.aA.e.a.b.m.a                                                                          q.c.aA.e.a.b.m.aA                                                                         q.c.aA.e.a.b.m.aG                                                                         q.c.aA.e.a.b.ao.a                         q.c.aA.e.a.b.o.aA                                                                         q.c.aA.e.a.b.o.aG                                                                         q.c.aA.e.a.b.E.a                                                                          q.c.aA.e.a.b.E.aA                         q.c.aA.e.a.b.E.aG                                                                         q.c.aA.e.a.b.R.a                                                                          q.c.aA.e.a.b.R.aA                                                                         q.c.aA.e.a.b.R.aG                         q.c.aA.e.a.b.aw.a                                                                         q.c.aA.e.a.b.aw.aA                                                                        q.c.aA.e.a.b.aw.aG                                                                        q.c.aA.e.a.b.aA.a                         q.c.aA.e.a.b.aA.aA                                                                        q.c.aA.e.a.b.aA.aG                                                                        q.c.aA.e.a.b.aG.a                                     q.c.aA.e.a.b.aG.aA                                                                        q.c.aA.e.a.b.aG.aG                                                                        q.c.aA.e.b.a.a.a                                                                          q.c.aA.e.b.a.a.aA                         q.c.aA.e.b.a.a.aG                                                                         q.c.aA.e.b.a.e.a                                                                          q.c.aA.e.b.a.e.aA                                                                         q.c.aA.e.b.a.e.aG                         q.c.aA.e.b.a.m.a                                                                          q.c.aA.e.b.a.m.aA                                                                         q.c.aA.e.b.a.m.aG                                                                         q.c.aA.e.b.a.ao.a                         q.c.aA.e.b.a.o.aA                                                                         q.c.aA.e.b.a.o.aG                                                                         q.c.aA.e.b.a.E.a                                                                          q.c.aA.e.b.a.E.aA                         q.c.aA.e.b.a.E.aG                                                                         q.c.aA.e.b.a.R.a                                                                          q.c.aA.e.b.a.R.aA                                                                         q.c.aA.e.b.a.R.aG                         q.c.aA.e.b.a.aw.a                                                                         q.c.aA.e.b.a.aw.aA                                                                        q.c.aA.e.b.a.aw.aG                                                                        q.c.aA.e.b.a.aA.a                         q.c.aA.e.b.a.aA.aA                                                                        q.c.aA.e.b.a.aA.aG                                                                        q.c.aA.e.b.a.aG.a                                     q.c.aA.e.b.a.aG.aA                                                                        q.c.aA.e.b.a.aG.aG                                                                        q.c.aA.e.b.b.a.a                                                                          q.c.aA.e.b.b.a.aA                         q.c.aA.e.b.b.a.aG                                                                         q.c.aA.e.b.b.e.a                                                                          q.c.aA.e.b.b.e.aA                                                                         q.c.aA.e.b.b.e.aG                         q.c.aA.e.b.b.m.a                                                                          q.c.aA.e.b.b.m.aA                                                                         q.c.aA.e.b.b.m.aG                                                                         q.c.aA.e.b.b.ao.a                         q.c.aA.e.b.b.o.aA                                                                         q.c.aA.e.b.b.o.aG                                                                         q.c.aA.e.b.b.E.a                                                                          q.c.aA.e.b.b.E.aA                         q.c.aA.e.b.b.E.aG                                                                         q.c.aA.e.b.b.R.a                                                                          q.c.aA.e.b.b.R.aA                                                                         q.c.aA.e.b.b.R.aG                         q.c.aA.e.b.b.aw.a                                                                         q.c.aA.e.b.b.aw.aA                                                                        q.c.aA.e.b.b.aw.aG                                                                        q.c.aA.e.b.b.aA.a                         q.c.aA.e.b.b.aA.aA                                                                        q.c.aA.e.b.b.aA.aG                                                                        q.c.aA.e.b.b.aG.a                                     q.c.aA.e.b.b.aG.aA                                                                        q.c.aA.e.b.b.aG.aG                                                                        q.c.aA.m.a.b.a.a                                                                          q.c.aA.m.a.b.a.aA                         q.c.aA.m.a.b.a.aG                                                                         q.c.aA.m.a.b.e.a                                                                          q.c.aA.m.a.b.e.aA                                                                         q.c.aA.m.a.b.e.aG                         q.c.aA.m.a.b.m.a                                                                          q.c.aA.m.a.b.m.aA                                                                         q.c.aA.m.a.b.m.aG                                                                         q.c.aA.m.a.b.ao.a                         q.c.aA.m.a.b.o.aA                                                                         q.c.aA.m.a.b.o.aG                                                                         q.c.aA.m.a.b.E.a                                                                          q.c.aA.m.a.b.E.aA                         q.c.aA.m.a.b.E.aG                                                                         q.c.aA.m.a.b.R.a                                                                          q.c.aA.m.a.b.R.aA                                                                         q.c.aA.m.a.b.R.aG                         q.c.aA.m.a.b.aw.a                                                                         q.c.aA.m.a.b.aw.aA                                                q.c.aA.m.a.b.aw.aG                                                                        q.c.aA.m.a.b.aA.a                                                                         q.c.aA.m.a.b.aA.aA                                    q.c.aA.m.a.b.aA.aG                                                                        q.c.aA.m.a.b.aG.a                                                                         q.c.aA.m.a.b.aG.aA                                    q.c.aA.m.a.b.aG.aG                                                                        q.c.aA.m.b.a.a.a                                                                          q.c.aA.m.b.a.a.aA                                                                         q.c.aA.m.b.a.a.aG                         q.c.aA.m.b.a.e.a                                                                          q.c.aA.m.b.a.e.aA                                                                         q.c.aA.m.b.a.e.aG                                                                         q.c.aA.m.b.a.m.a                          q.c.aA.m.b.a.m.aA                                                                         q.c.aA.m.b.a.m.aG                                                                         q.c.aA.m.b.a.ao.a                                                                         q.c.aA.m.b.a.o.aA                         q.c.aA.m.b.a.o.aG                                                                         q.c.aA.m.b.a.E.a                                                                          q.c.aA.m.b.a.E.aA                                                                         q.c.aA.m.b.a.E.aG                         q.c.aA.m.b.a.R.a                                                                          q.c.aA.m.b.a.R.aA                                                                         q.c.aA.m.b.a.R.aG                                                                         q.c.aA.m.b.a.aw.a                         q.c.aA.m.b.a.aw.aA      q.c.aA.m.b.a.aw.aG                                                                        q.c.aA.m.b.a.aA.a                         q.c.aA.m.b.a.aA.aA      q.c.aA.m.b.a.aA.aG                                                                        q.c.aA.m.b.a.aG.a                         q.c.aA.m.b.a.aG.aA                                                                        q.c.aA.m.b.a.aG.aG                                                                        q.c.aA.m.b.b.a.a                                                                          q.c.aA.m.b.b.a.aA                         q.c.aA.m.b.b.a.aG                                                                         q.c.aA.m.b.b.e.a                                                                          q.c.aA.m.b.b.e.aA                                                                         q.c.aA.m.b.b.e.aG                         q.c.aA.m.b.b.m.a                                                                          q.c.aA.m.b.b.m.aA                                                                         q.c.aA.m.b.b.m.aG                                                                         q.c.aA.m.b.b.ao.a                         q.c.aA.m.b.b.o.aA                                                                         q.c.aA.m.b.b.o.aG                                                                         q.c.aA.m.b.b.E.a                                                                          q.c.aA.m.b.b.E.aA                         q.c.aA.m.b.b.E.aG                                                                         q.c.aA.m.b.b.R.a                                                                          q.c.aA.m.b.b.R.aA                                                                         q.c.aA.m.b.b.R.aG                         q.c.aA.m.b.b.aw.a                                                                         q.c.aA.m.b.b.aw.aA                                                q.c.aA.m.b.b.aw.aG                                                                        q.c.aA.m.b.b.aA.a                                                                         q.c.aA.m.b.b.aA.aA                                    q.c.aA.m.b.b.aA.aG                                                                        q.c.aA.m.b.b.aG.a                                                                         q.c.aA.m.b.b.aG.aA                                    q.c.aA.m.b.b.aG.aG                                                                        q.c.aA.o.a.b.a.a                                                                          q.c.aA.o.a.b.a.aA                                                                         q.c.aA.o.a.b.a.aG                         q.c.aA.o.a.b.e.a                                                                          q.c.aA.o.a.b.e.aA                                                                         q.c.aA.o.a.b.e.aG                                                                         q.c.aA.o.a.b.m.a                          q.c.aA.o.a.b.m.aA                                                                         q.c.aA.o.a.b.m.aG                                                                         q.c.aA.o.a.b.ao.a                                                                         q.c.aA.o.a.b.o.aA                         q.c.aA.o.a.b.o.aG                                                                         q.c.aA.o.a.b.E.a                                                                          q.c.aA.o.a.b.E.aA                                                                         q.c.aA.o.a.b.E.aG                         q.c.aA.o.a.b.R.a                                                                          q.c.aA.o.a.b.R.aA                                                                         q.c.aA.o.a.b.R.aG                                                                         q.c.aA.o.a.b.aw.a                         q.c.aA.o.a.b.aw.aA                                                                        q.c.aA.o.a.b.aw.aG                                                                        q.c.aA.o.a.b.aA.a                                     q.c.aA.o.a.b.aA.aA                                                                        q.c.aA.o.a.b.aA.aG                                                                        q.c.aA.o.a.b.aG.a                                     q.c.aA.o.a.b.aG.aA                                                                        q.c.aA.o.a.b.aG.aG                                                                        q.c.aA.o.b.a.a.a                                                                          q.c.aA.o.b.a.a.aA                         q.c.aA.o.b.a.a.aG                                                                         q.c.aA.o.b.a.e.a                                                                          q.c.aA.o.b.a.e.aA                                                                         q.c.aA.o.b.a.e.aG                         q.c.aA.o.b.a.m.a                                                                          q.c.aA.o.b.a.m.aA                                                                         q.c.aA.o.b.a.m.aG                                                                         q.c.aA.o.b.a.ao.a                         q.c.aA.o.b.a.o.aA                                                                         q.c.aA.o.b.a.o.aG                                                                         q.c.aA.o.b.a.E.a                                                                          q.c.aA.o.b.a.E.aA                         q.c.aA.o.b.a.E.aG                                                                         q.c.aA.o.b.a.R.a                                                                          q.c.aA.o.b.a.R.aA                                                                         q.c.aA.o.b.a.R.aG                         q.c.aA.o.b.a.aw.a                                                                         q.c.aA.o.b.a.aw.aA                                                                        q.c.aA.o.b.a.aw.aG                                                                        q.c.aA.o.b.a.aA.a                         q.c.aA.o.b.a.aA.aA                                                                        q.c.aA.o.b.a.aA.aG                                                                        q.c.aA.o.b.a.aG.a                                     q.c.aA.o.b.a.aG.aA                                                                        q.c.aA.o.b.a.aG.aG                                                                        q.c.aA.o.b.b.a.a                                                                          q.c.aA.o.b.b.a.aA                         q.c.aA.o.b.b.a.aG                                                                         q.c.aA.o.b.b.e.a                                                                          q.c.aA.o.b.b.e.aA                                                                         q.c.aA.o.b.b.e.aG                         q.c.aA.o.b.b.m.a                                                                          q.c.aA.o.b.b.m.aA                                                                         q.c.aA.o.b.b.m.aG                                                                         q.c.aA.o.b.b.ao.a                         q.c.aA.o.b.b.o.aA                                                                         q.c.aA.o.b.b.o.aG                                                                         q.c.aA.o.b.b.E.a                                                                          q.c.aA.o.b.b.E.aA                         q.c.aA.o.b.b.E.aG                                                                         q.c.aA.o.b.b.R.a                                                                          q.c.aA.o.b.b.R.aA                                                                         q.c.aA.o.b.b.R.aG                         q.c.aA.o.b.b.aw.a                                                                         q.c.aA.o.b.b.aw.aA                                                                        q.c.aA.o.b.b.aw.aG                                                                        q.c.aA.o.b.b.aA.a                         q.c.aA.o.b.b.aA.aA                                                                        q.c.aA.o.b.b.aA.aG                                                                        q.c.aA.o.b.b.aG.a                                     q.c.aA.o.b.b.aG.aA                                                                        q.c.aA.o.b.b.aG.aG                                                                        q.c.aA.E.a.b.a.a                                                                          q.c.aA.E.a.b.a.aA                         q.c.aA.E.a.b.a.aG                                                                         q.c.aA.E.a.b.e.a                                                                          q.c.aA.E.a.b.e.aA                                                                         q.c.aA.E.a.b.e.aG                         q.c.aA.E.a.b.m.a                                                                          q.c.aA.E.a.b.m.aA                                                                         q.c.aA.E.a.b.m.aG                                                                         q.c.aA.E.a.b.ao.a                         q.c.aA.E.a.b.o.aA                                                                         q.c.aA.E.a.b.o.aG                                                                         q.c.aA.E.a.b.E.a                                                                          q.c.aA.E.a.b.E.aA                         q.c.aA.E.a.b.E.aG                                                                         q.c.aA.E.a.b.R.a                                                                          q.c.aA.E.a.b.R.aA                                                                         q.c.aA.E.a.b.R.aG                         q.c.aA.E.a.b.aw.a                                                                         q.c.aA.E.a.b.aw.aA                                                                        q.c.aA.E.a.b.aw.aG                                                                        q.c.aA.E.a.b.aA.a                         q.c.aA.E.a.b.aA.aA                                                                        q.c.aA.E.a.b.aA.aG                                                                        q.c.aA.E.a.b.aG.a                                     q.c.aA.E.a.b.aG.aA                                                                        q.c.aA.E.a.b.aG.aG                                                                        q.c.aA.E.b.a.a.a                                                                          q.c.aA.E.b.a.a.aA                         q.c.aA.E.b.a.a.aG                                                                         q.c.aA.E.b.a.e.a                                                                          q.c.aA.E.b.a.e.aA                                                                         q.c.aA.E.b.a.e.aG                         q.c.aA.E.b.a.m.a                                                                          q.c.aA.E.b.a.m.aA                                                                         q.c.aA.E.b.a.m.aG                                                                         q.c.aA.E.b.a.ao.a                         q.c.aA.E.b.a.o.aA                                                                         q.c.aA.E.b.a.o.aG                                                                         q.c.aA.E.b.a.E.a                                                                          q.c.aA.E.b.a.E.aA                         q.c.aA.E.b.a.E.aG                                                                         q.c.aA.E.b.a.R.a                                                                          q.c.aA.E.b.a.R.aA                                                                         q.c.aA.E.b.a.R.aG                         q.c.aA.E.b.a.aw.a                                                                         q.c.aA.E.b.a.aw.aA                                                                        q.c.aA.E.b.a.aw.aG                                                                        q.c.aA.E.b.a.aA.a                         q.c.aA.E.b.a.aA.aA                                                                        q.c.aA.E.b.a.aA.aG                                                                        q.c.aA.E.b.a.aG.a                                     q.c.aA.E.b.a.aG.aA                                                                        q.c.aA.E.b.a.aG.aG                                                                        q.c.aA.E.b.b.a.a                                                                          q.c.aA.E.b.b.a.aA                         q.c.aA.E.b.b.a.aG                                                                         q.c.aA.E.b.b.e.a                                                                          q.c.aA.E.b.b.e.aA                                                                         q.c.aA.E.b.b.e.aG                         q.c.aA.E.b.b.m.a                                                                          q.c.aA.E.b.b.m.aA                                                                         q.c.aA.E.b.b.m.aG                                                                         q.c.aA.E.b.b.ao.a                         q.c.aA.E.b.b.o.aA                                                                         q.c.aA.E.b.b.o.aG                                                                         q.c.aA.E.b.b.E.a                                                                          q.c.aA.E.b.b.E.aA                         q.c.aA.E.b.b.E.aG                                                                         q.c.aA.E.b.b.R.a                                                                          q.c.aA.E.b.b.R.aA                                                                         q.c.aA.E.b.b.R.aG                         q.c.aA.E.b.b.aw.a                                                                         q.c.aA.E.b.b.aw.aA                                                                        q.c.aA.E.b.b.aw.aG                                                                        q.c.aA.E.b.b.aA.a                         q.c.aA.E.b.b.aA.aA                                                                        q.c.aA.E.b.b.aA.aG                                                                        q.c.aA.E.b.b.aG.a                                     q.c.aA.E.b.b.aG.aA                                                                        q.c.aA.E.b.b.aG.aG                                                                        q.c.aA.R.a.b.a.a                                                                          q.c.aA.R.a.b.a.aA                         q.c.aA.R.a.b.a.aG                                                                         q.c.aA.R.a.b.e.a                                                                          q.c.aA.R.a.b.e.aA                                                                         q.c.aA.R.a.b.e.aG                         q.c.aA.R.a.b.m.a                                                                          q.c.aA.R.a.b.m.aA                                                                         q.c.aA.R.a.b.m.aG                                                                         q.c.aA.R.a.b.ao.a                         q.c.aA.R.a.b.o.aA                                                                         q.c.aA.R.a.b.o.aG                                                                         q.c.aA.R.a.b.E.a                                                                          q.c.aA.R.a.b.E.aA                         q.c.aA.R.a.b.E.aG                                                                         q.c.aA.R.a.b.R.a                                                                          q.c.aA.R.a.b.R.aA                                                                         q.c.aA.R.a.b.R.aG                         q.c.aA.R.a.b.aw.a                                                                         q.c.aA.R.a.b.aw.aA                                                                        q.c.aA.R.a.b.aw.aG                                                                        q.c.aA.R.a.b.aA.a                         q.c.aA.R.a.b.aA.aA                                                                        q.c.aA.R.a.b.aA.aG                                                                        q.c.aA.R.a.b.aG.a                                     q.c.aA.R.a.b.aG.aA                                                                        q.c.aA.R.a.b.aG.aG                                                                        q.c.aA.R.b.a.a.a                                                                          q.c.aA.R.b.a.a.aA                         q.c.aA.R.b.a.a.aG                                                                         q.c.aA.R.b.a.e.a                                                                          q.c.aA.R.b.a.e.aA                                                                         q.c.aA.R.b.a.e.aG                         q.c.aA.R.b.a.m.a                                                                          q.c.aA.R.b.a.m.aA                                                                         q.c.aA.R.b.a.m.aG                                                                         q.c.aA.R.b.a.ao.a                         q.c.aA.R.b.a.o.aA                                                                         q.c.aA.R.b.a.o.aG                                                                         q.c.aA.R.b.a.E.a                                                                          q.c.aA.R.b.a.E.aA                         q.c.aA.R.b.a.E.aG                                                                         q.c.aA.R.b.a.R.a                                                                          q.c.aA.R.b.a.R.aA                                                                         q.c.aA.R.b.a.R.aG                         q.c.aA.R.b.a.aw.a                                                                         q.c.aA.R.b.a.aw.aA                                                                        q.c.aA.R.b.a.aw.aG                                                                        q.c.aA.R.b.a.aA.a                         q.c.aA.R.b.a.aA.aA                                                                        q.c.aA.R.b.a.aA.aG                                                                        q.c.aA.R.b.a.aG.a                                     q.c.aA.R.b.a.aG.aA                                                                        q.c.aA.R.b.a.aG.aG                                                                        q.c.aA.R.b.b.a.a                                                                          q.c.aA.R.b.b.a.aA                         q.c.aA.R.b.b.a.aG                                                                         q.c.aA.R.b.b.e.a                                                                          q.c.aA.R.b.b.e.aA                                                                         q.c.aA.R.b.b.e.aG                         q.c.aA.R.b.b.m.a                                                                          q.c.aA.R.b.b.m.aA                                                                         q.c.aA.R.b.b.m.aG                                                                         q.c.aA.R.b.b.ao.a                         q.c.aA.R.b.b.o.aA                                                                         q.c.aA.R.b.b.o.aG                                                                         q.c.aA.R.b.b.E.a                                                                          q.c.aA.R.b.b.E.aA                         q.c.aA.R.b.b.E.aG                                                                         q.c.aA.R.b.b.R.a                                                                          q.c.aA.R.b.b.R.aA                                                                         q.c.aA.R.b.b.R.aG                         q.c.aA.R.b.b.aw.a                                                                         q.c.aA.R.b.b.aw.aA                                                                        q.c.aA.R.b.b.aw.aG                                                                        q.c.aA.R.b.b.aA.a                         q.c.aA.R.b.b.aA.aA                                                                        q.c.aA.R.b.b.aA.aG                                                                        q.c.aA.R.b.b.aG.a                                     q.c.aA.R.b.b.aG.aA                                                                        q.c.aA.R.b.b.aG.aG                                                                        q.c.aA.aw.a.b.a.a                                                                         q.c.aA.aw.a.b.a.aA                        q.c.aA.aw.a.b.a.aG                                                                        q.c.aA.aw.a.b.e.a                                                                         q.c.aA.aw.a.b.e.aA                                                                        q.c.aA.aw.a.b.e.aG                        q.c.aA.aw.a.b.m.a                                                                         q.c.aA.aw.a.b.m.aA                                                                        q.c.aA.aw.a.b.m.aG                                                                        q.c.aA.aw.a.b.ao.a                        q.c.aA.aw.a.b.o.aA                                                                        q.c.aA.aw.a.b.o.aG                                                                        q.c.aA.aw.a.b.E.a                                     q.c.aA.aw.a.b.E.aA                                                                        q.c.aA.aw.a.b.E.aG                                                                        q.c.aA.aw.a.b.R.a                                     q.c.aA.aw.a.b.R.aA                                                                        q.c.aA.aw.a.b.R.aG                                                                        q.c.aA.aw.a.b.aw.a                                    q.c.aA.aw.a.b.aw.aA     q.c.aA.aw.a.b.aw.aG                                   q.c.aA.aw.a.b.aA.a                                                                        q.c.aA.aw.a.b.aA.aA                                               q.c.aA.aw.a.b.aA.aG     q.c.aA.aw.a.b.aG.a                                    q.c.aA.aw.a.b.aG.aA     q.c.aA.aw.a.b.aG.aG                                   q.c.aA.aw.b.a.a.a                                                                         q.c.aA.aw.b.a.a.aA                                                                        q.c.aA.aw.b.a.a.aG                                                                        q.c.aA.aw.b.a.e.a                         q.c.aA.aw.b.a.e.aA                                                                        q.c.aA.aw.b.a.e.aG                                                                        q.c.aA.aw.b.a.m.a                                     q.c.aA.aw.b.a.m.aA      q.c.aA.aw.b.a.m.aG                                                                        q.c.aA.aw.b.a.ao.a                        q.c.aA.aw.b.a.o.aA                                                                        q.c.aA.aw.b.a.o.aG                                                                        q.c.aA.aw.b.a.E.a                                     q.c.aA.aw.b.a.E.aA                                                                        q.c.aA.aw.b.a.E.aG                                                                        q.c.aA.aw.b.a.R.a                                     q.c.aA.aw.b.a.R.aA                                                                        q.c.aA.aw.b.a.R.aG                                                                        q.c.aA.aw.b.a.aw.a                                    q.c.aA.aw.b.a.aw.aA     q.c.aA.aw.b.a.aw.aG                                   q.c.aA.aw.b.a.aA.a                                                                        q.c.aA.aw.b.a.aA.aA                                               q.c.aA.aw.b.a.aA.aG     q.c.aA.aw.b.a.aG.a                                    q.c.aA.aw.b.a.aG.aA     q.c.aA.aw.b.a.aG.aG                                   q.c.aA.aw.b.b.a.a                                                                         q.c.aA.aw.b.b.a.aA                                                                        q.c.aA.aw.b.b.a.aG                                                                        q.c.aA.aw.b.b.e.a                         q.c.aA.aw.b.b.e.aA                                                                        q.c.aA.aw.b.b.e.aG                                                                        q.c.aA.aw.b.b.m.a                                     q.c.aA.aw.b.b.m.aA      q.c.aA.aw.b.b.m.aG                                                                        q.c.aA.aw.b.b.ao.a                        q.c.aA.aw.b.b.o.aA                                                                        q.c.aA.aw.b.b.o.aG                                                                        q.c.aA.aw.b.b.E.a                                     q.c.aA.aw.b.b.E.aA                                                                        q.c.aA.aw.b.b.E.aG                                                                        q.c.aA.aw.b.b.R.a                                     q.c.aA.aw.b.b.R.aA                                                                        q.c.aA.aw.b.b.R.aG                                                                        q.c.aA.aw.b.b.aw.a                                    q.c.aA.aw.b.b.aw.aA     q.c.aA.aw.b.b.aw.aG                                   q.c.aA.aw.b.b.aA.a                                                                        q.c.aA.aw.b.b.aA.aA                                               q.c.aA.aw.b.b.aA.aG     q.c.aA.aw.b.b.aG.a                                    q.c.aA.aw.b.b.aG.aA     q.c.aA.aw.b.b.aG.aG                                   q.c.aA.aA.a.b.a.a                                                                         q.c.aA.aA.a.b.a.aA                                                                        q.c.aA.aA.a.b.a.aG                                                                        q.c.aA.aA.a.b.e.a                         q.c.aA.aA.a.b.e.aA                                                                        q.c.aA.aA.a.b.e.aG                                                                        q.c.aA.aA.a.b.m.a                                     q.c.aA.aA.a.b.m.aA      q.c.aA.aA.a.b.m.aG                                                                        q.c.aA.aA.a.b.ao.a                        q.c.aA.aA.a.b.o.aA                                                                        q.c.aA.aA.a.b.o.aG                                                                        q.c.aA.aA.a.b.E.a                                     q.c.aA.aA.a.b.E.aA                                                                        q.c.aA.aA.a.b.E.aG                                                                        q.c.aA.aA.a.b.R.a                                     q.c.aA.aA.a.b.R.aA                                                                        q.c.aA.aA.a.b.R.aG                                                                        q.c.aA.aA.a.b.aw.a                                    q.c.aA.aA.a.b.aw.aA     q.c.aA.aA.a.b.aw.aG                                   q.c.aA.aA.a.b.aA.a                                                                        q.c.aA.aA.a.b.aA.aA                                               q.c.aA.aA.a.b.aA.aG     q.c.aA.aA.a.b.aG.a                                    q.c.aA.aA.a.b.aG.aA     q.c.aA.aA.a.b.aG.aG                                   q.c.aA.aA.b.a.a.a                                                                         q.c.aA.aA.b.a.a.aA                                                                        q.c.aA.aA.b.a.a.aG                                                                        q.c.aA.aA.b.a.e.a                         q.c.aA.aA.b.a.e.aA                                                                        q.c.aA.aA.b.a.e.aG                                                                        q.c.aA.aA.b.a.m.a                                     q.c.aA.aA.b.a.m.aA      q.c.aA.aA.b.a.m.aG                                                                        q.c.aA.aA.b.a.ao.a                        q.c.aA.aA.b.a.o.aA                                                                        q.c.aA.aA.b.a.o.aG                                                                        q.c.aA.aA.b.a.E.a                                     q.c.aA.aA.b.a.E.aA                                                                        q.c.aA.aA.b.a.E.aG                                                                        q.c.aA.aA.b.a.R.a                                     q.c.aA.aA.b.a.R.aA                                                                        q.c.aA.aA.b.a.R.aG                                                                        q.c.aA.aA.b.a.aw.a                                    q.c.aA.aA.b.a.aw.aA     q.c.aA.aA.b.a.aw.aG                                   q.c.aA.aA.b.a.aA.a                                                                        q.c.aA.aA.b.a.aA.aA                                               q.c.aA.aA.b.a.aA.aG     q.c.aA.aA.b.a.aG.a                                    q.c.aA.aA.b.a.aG.aA     q.c.aA.aA.b.a.aG.aG                                   q.c.aA.aA.b.b.a.a                                                                         q.c.aA.aA.b.b.a.aA                                                                        q.c.aA.aA.b.b.a.aG                                                                        q.c.aA.aA.b.b.e.a                         q.c.aA.aA.b.b.e.aA                                                                        q.c.aA.aA.b.b.e.aG                                                                        q.c.aA.aA.b.b.m.a                                     q.c.aA.aA.b.b.m.aA      q.c.aA.aA.b.b.m.aG                                                                        q.c.aA.aA.b.b.ao.a                        q.c.aA.aA.b.b.o.aA                                                                        q.c.aA.aA.b.b.o.aG                                                                        q.c.aA.aA.b.b.E.a                                     q.c.aA.aA.b.b.E.aA                                                                        q.c.aA.aA.b.b.E.aG                                                                        q.c.aA.aA.b.b.R.a                                     q.c.aA.aA.b.b.R.aA                                                                        q.c.aA.aA.b.b.R.aG                                                                        q.c.aA.aA.b.b.aw.a                                    q.c.aA.aA.b.b.aw.aA     q.c.aA.aA.b.b.aw.aG                                   q.c.aA.aA.b.b.aA.a                                                                        q.c.aA.aA.b.b.aA.aA                                               q.c.aA.aA.b.b.aA.aG     q.c.aA.aA.b.b.aG.a                                    q.c.aA.aA.b.b.aG.aA     q.c.aA.aA.b.b.aG.aG                                   q.c.aA.aG.a.b.a.a                                                                         q.c.aA.aG.a.b.a.aA                                                                        q.c.aA.aG.a.b.a.aG                                                                        q.c.aA.aG.a.b.e.a                         q.c.aA.aG.a.b.e.aA                                                                        q.c.aA.aG.a.b.e.aG                                                                        q.c.aA.aG.a.b.m.a                                     q.c.aA.aG.a.b.m.aA      q.c.aA.aG.a.b.m.aG                                                                        q.c.aA.aG.a.b.ao.a                        q.c.aA.aG.a.b.o.aA                                                                        q.c.aA.aG.a.b.o.aG                                                                        q.c.aA.aG.a.b.E.a                                     q.c.aA.aG.a.b.E.aA                                                                        q.c.aA.aG.a.b.E.aG                                                                        q.c.aA.aG.a.b.R.a                                     q.c.aA.aG.a.b.R.aA                                                                        q.c.aA.aG.a.b.R.aG                                                                        q.c.aA.aG.a.b.aw.a                                    q.c.aA.aG.a.b.aw.aA     q.c.aA.aG.a.b.aw.aG                                   q.c.aA.aG.a.b.aA.a                                                                        q.c.aA.aG.a.b.aA.aA                                               q.c.aA.aG.a.b.aA.aG     q.c.aA.aG.a.b.aG.a                                    q.c.aA.aG.a.b.aG.aA     q.c.aA.aG.a.b.aG.aG                                   q.c.aA.aG.b.a.a.a                                                                         q.c.aA.aG.b.a.a.aA                                                                        q.c.aA.aG.b.a.a.aG                                                                        q.c.aA.aG.b.a.e.a                         q.c.aA.aG.b.a.e.aA                                                                        q.c.aA.aG.b.a.e.aG                                                                        q.c.aA.aG.b.a.m.a                                     q.c.aA.aG.b.a.m.aA      q.c.aA.aG.b.a.m.aG                                                                        q.c.aA.aG.b.a.ao.a                        q.c.aA.aG.b.a.o.aA                                                                        q.c.aA.aG.b.a.o.aG                                                                        q.c.aA.aG.b.a.E.a                                     q.c.aA.aG.b.a.E.aA                                                                        q.c.aA.aG.b.a.E.aG                                                                        q.c.aA.aG.b.a.R.a                                     q.c.aA.aG.b.a.R.aA                                                                        q.c.aA.aG.b.a.R.aG                                                                        q.c.aA.aG.b.a.aw.a                                    q.c.aA.aG.b.a.aw.aA     q.c.aA.aG.b.a.aw.aG                                   q.c.aA.aG.b.a.aA.a                                                                        q.c.aA.aG.b.a.aA.aA                                               q.c.aA.aG.b.a.aA.aG     q.c.aA.aG.b.a.aG.a                                    q.c.aA.aG.b.a.aG.aA     q.c.aA.aG.b.a.aG.aG                                   q.c.aA.aG.b.b.a.a                                                                         q.c.aA.aG.b.b.a.aA                                                                        q.c.aA.aG.b.b.a.aG                                                                        q.c.aA.aG.b.b.e.a                         q.c.aA.aG.b.b.e.aA                                                                        q.c.aA.aG.b.b.e.aG                                                                        q.c.aA.aG.b.b.m.a                                     q.c.aA.aG.b.b.m.aA      q.c.aA.aG.b.b.m.aG                                                                        q.c.aA.aG.b.b.ao.a                        q.c.aA.aG.b.b.o.aA                                                                        q.c.aA.aG.b.b.o.aG                                                                        q.c.aA.aG.b.b.E.a                                     q.c.aA.aG.b.b.E.aA                                                                        q.c.aA.aG.b.b.E.aG                                                                        q.c.aA.aG.b.b.R.a                                     q.c.aA.aG.b.b.R.aA                                                                        q.c.aA.aG.b.b.R.aG                                                                        q.c.aA.aG.b.b.aw.a                                    q.c.aA.aG.b.b.aw.aA     q.c.aA.aG.b.b.aw.aG                                   q.c.aA.aG.b.b.aA.a                                                                        q.c.aA.aG.b.b.aA.aA                                               q.c.aA.aG.b.b.aA.aG     q.c.aA.aG.b.b.aG.a                                    q.c.aA.aG.b.b.aG.aA     q.c.aA.aG.b.b.aG.aG                                                                       q.c.aG.a.a.b.a.a                          q.c.aG.a.a.b.a.aA                                                                         q.c.aG.a.a.b.a.aG                                                                         q.c.aG.a.a.b.e.a                                                                          q.c.aG.a.a.b.e.aA                         q.c.aG.a.a.b.e.aG                                                                         q.c.aG.a.a.b.m.a                                                                          q.c.aG.a.a.b.m.aA                                                                         q.c.aG.a.a.b.m.aG                         q.c.aG.a.a.b.ao.a                                                                         q.c.aG.a.a.b.o.aA                                                                         q.c.aG.a.a.b.o.aG                                                                         q.c.aG.a.a.b.E.a                          q.c.aG.a.a.b.E.aA                                                                         q.c.aG.a.a.b.E.aG                                                                         q.c.aG.a.a.b.R.a                                                                          q.c.aG.a.a.b.R.aA                         q.c.aG.a.a.b.R.aG                                                                         q.c.aG.a.a.b.aw.a                                                                         q.c.aG.a.a.b.aw.aA                                                                        q.c.aG.a.a.b.aw.aG                        q.c.aG.a.a.b.aA.a                                                                         q.c.aG.a.a.b.aA.aA                                                                        q.c.aG.a.a.b.aA.aG                                                                        q.c.aG.a.a.b.aG.a                         q.c.aG.a.a.b.aG.aA                                                                        q.c.aG.a.a.b.aG.aG                                                                        q.c.aG.a.b.a.a.a                                                                          q.c.aG.a.b.a.a.aA                         q.c.aG.a.b.a.a.aG                                                                         q.c.aG.a.b.a.e.a                                                                          q.c.aG.a.b.a.e.aA                                                                         q.c.aG.a.b.a.e.aG                         q.c.aG.a.b.a.m.a                                                                          q.c.aG.a.b.a.m.aA                                                                         q.c.aG.a.b.a.m.aG                                                                         q.c.aG.a.b.a.ao.a                         q.c.aG.a.b.a.o.aA                                                                         q.c.aG.a.b.a.o.aG                                                                         q.c.aG.a.b.a.E.a                                                                          q.c.aG.a.b.a.E.aA                         q.c.aG.a.b.a.E.aG                                                                         q.c.aG.a.b.a.R.a                                                                          q.c.aG.a.b.a.R.aA                                                                         q.c.aG.a.b.a.R.aG                         q.c.aG.a.b.a.aw.a                                                                         q.c.aG.a.b.a.aw.aA                                                                        q.c.aG.a.b.a.aw.aG                                                                        q.c.aG.a.b.a.aA.a                         q.c.aG.a.b.a.aA.aA                                                                        q.c.aG.a.b.a.aA.aG                                                                        q.c.aG.a.b.a.aG.a                                                                         q.c.aG.a.b.a.aG.aA                        q.c.aG.a.b.a.aG.aG                                                                        q.c.aG.a.b.b.a.a                                                                          q.c.aG.a.b.b.a.aA                                                                         q.c.aG.a.b.b.a.aG                         q.c.aG.a.b.b.e.a                                                                          q.c.aG.a.b.b.e.aA                                                                         q.c.aG.a.b.b.e.aG                                                                         q.c.aG.a.b.b.m.a                          q.c.aG.a.b.b.m.aA                                                                         q.c.aG.a.b.b.m.aG                                                                         q.c.aG.a.b.b.ao.a                                                                         q.c.aG.a.b.b.o.aA                         q.c.aG.a.b.b.o.aG                                                                         q.c.aG.a.b.b.E.a                                                                          q.c.aG.a.b.b.E.aA                                                                         q.c.aG.a.b.b.E.aG                         q.c.aG.a.b.b.R.a                                                                          q.c.aG.a.b.b.R.aA                                                                         q.c.aG.a.b.b.R.aG                                                                         q.c.aG.a.b.b.aw.a                         q.c.aG.a.b.b.aw.aA                                                                        q.c.aG.a.b.b.aw.aG                                                                        q.c.aG.a.b.b.aA.a                                     q.c.aG.a.b.b.aA.aA                                                                        q.c.aG.a.b.b.aA.aG                                                                        q.c.aG.a.b.b.aG.a                                                                         q.c.aG.a.b.b.aG.aA                        q.c.aG.a.b.b.aG.aG                                                                        q.c.aG.e.a.b.a.a                                                                          q.c.aG.e.a.b.a.aA                                                                         q.c.aG.e.a.b.a.aG                         q.c.aG.e.a.b.e.a                                                                          q.c.aG.e.a.b.e.aA                                                                         q.c.aG.e.a.b.e.aG                                                                         q.c.aG.e.a.b.m.a                          q.c.aG.e.a.b.m.aA                                                                         q.c.aG.e.a.b.m.aG                                                                         q.c.aG.e.a.b.ao.a                                                                         q.c.aG.e.a.b.o.aA                         q.c.aG.e.a.b.o.aG                                                                         q.c.aG.e.a.b.E.a                                                                          q.c.aG.e.a.b.E.aA                                                                         q.c.aG.e.a.b.E.aG                         q.c.aG.e.a.b.R.a                                                                          q.c.aG.e.a.b.R.aA                                                                         q.c.aG.e.a.b.R.aG                                                                         q.c.aG.e.a.b.aw.a                         q.c.aG.e.a.b.aw.aA                                                                        q.c.aG.e.a.b.aw.aG                                                                        q.c.aG.e.a.b.aA.a                                     q.c.aG.e.a.b.aA.aA                                                                        q.c.aG.e.a.b.aA.aG                                                                        q.c.aG.e.a.b.aG.a                                                                         q.c.aG.e.a.b.aG.aA                        q.c.aG.e.a.b.aG.aG                                                                        q.c.aG.e.b.a.a.a                                                                          q.c.aG.e.b.a.a.aA                                                                         q.c.aG.e.b.a.a.aG                         q.c.aG.e.b.a.e.a                                                                          q.c.aG.e.b.a.e.aA                                                                         q.c.aG.e.b.a.e.aG                                                                         q.c.aG.e.b.a.m.a                          q.c.aG.e.b.a.m.aA                                                                         q.c.aG.e.b.a.m.aG                                                                         q.c.aG.e.b.a.ao.a                                                                         q.c.aG.e.b.a.o.aA                         q.c.aG.e.b.a.o.aG                                                                         q.c.aG.e.b.a.E.a                                                                          q.c.aG.e.b.a.E.aA                                                                         q.c.aG.e.b.a.E.aG                         q.c.aG.e.b.a.R.a                                                                          q.c.aG.e.b.a.R.aA                                                                         q.c.aG.e.b.a.R.aG                                                                         q.c.aG.e.b.a.aw.a                         q.c.aG.e.b.a.aw.aA                                                                        q.c.aG.e.b.a.aw.aG                                                                        q.c.aG.e.b.a.aA.a                                     q.c.aG.e.b.a.aA.aA                                                                        q.c.aG.e.b.a.aA.aG                                                                        q.c.aG.e.b.a.aG.a                                                                         q.c.aG.e.b.a.aG.aA                        q.c.aG.e.b.a.aG.aG                                                                        q.c.aG.e.b.b.a.a                                                                          q.c.aG.e.b.b.a.aA                                                                         q.c.aG.e.b.b.a.aG                         q.c.aG.e.b.b.e.a                                                                          q.c.aG.e.b.b.e.aA                                                                         q.c.aG.e.b.b.e.aG                                                                         q.c.aG.e.b.b.m.a                          q.c.aG.e.b.b.m.aA                                                                         q.c.aG.e.b.b.m.aG                                                                         q.c.aG.e.b.b.ao.a                                                                         q.c.aG.e.b.b.o.aA                         q.c.aG.e.b.b.o.aG                                                                         q.c.aG.e.b.b.E.a                                                                          q.c.aG.e.b.b.E.aA                                                                         q.c.aG.e.b.b.E.aG                         q.c.aG.e.b.b.R.a                                                                          q.c.aG.e.b.b.R.aA                                                                         q.c.aG.e.b.b.R.aG                                                                         q.c.aG.e.b.b.aw.a                         q.c.aG.e.b.b.aw.aA                                                                        q.c.aG.e.b.b.aw.aG                                                                        q.c.aG.e.b.b.aA.a                                     q.c.aG.e.b.b.aA.aA                                                                        q.c.aG.e.b.b.aA.aG                                                                        q.c.aG.e.b.b.aG.a                                                                         q.c.aG.e.b.b.aG.aA                        q.c.aG.e.b.b.aG.aG                                                                        q.c.aG.m.a.b.a.a                                                                          q.c.aG.m.a.b.a.aA                                                                         q.c.aG.m.a.b.a.aG                         q.c.aG.m.a.b.e.a                                                                          q.c.aG.m.a.b.e.aA                                                                         q.c.aG.m.a.b.e.aG                                                                         q.c.aG.m.a.b.m.a                          q.c.aG.m.a.b.m.aA                                                                         q.c.aG.m.a.b.m.aG                                                                         q.c.aG.m.a.b.ao.a                                                                         q.c.aG.m.a.b.o.aA                         q.c.aG.m.a.b.o.aG                                                                         q.c.aG.m.a.b.E.a                                                                          q.c.aG.m.a.b.E.aA                                                                         q.c.aG.m.a.b.E.aG                         q.c.aG.m.a.b.R.a                                                                          q.c.aG.m.a.b.R.aA                                                                         q.c.aG.m.a.b.R.aG                                                                         q.c.aG.m.a.b.aw.a                         q.c.aG.m.a.b.aw.aA                                                                        q.c.aG.m.a.b.aw.aG                                                                        q.c.aG.m.a.b.aA.a                                     q.c.aG.m.a.b.aA.aA                                                                        q.c.aG.m.a.b.aA.aG                                                                        q.c.aG.m.a.b.aG.a                                     q.c.aG.m.a.b.aG.aA                                                                        q.c.aG.m.a.b.aG.aG                                                                        q.c.aG.m.b.a.a.a                                                                          q.c.aG.m.b.a.a.aA                         q.c.aG.m.b.a.a.aG                                                                         q.c.aG.m.b.a.e.a                                                                          q.c.aG.m.b.a.e.aA                                                                         q.c.aG.m.b.a.e.aG                         q.c.aG.m.b.a.m.a                                                                          q.c.aG.m.b.a.m.aA                                                                         q.c.aG.m.b.a.m.aG                                                                         q.c.aG.m.b.a.ao.a                         q.c.aG.m.b.a.o.aA                                                                         q.c.aG.m.b.a.o.aG                                                                         q.c.aG.m.b.a.E.a                                                                          q.c.aG.m.b.a.E.aA                         q.c.aG.m.b.a.E.aG                                                                         q.c.aG.m.b.a.R.a                                                                          q.c.aG.m.b.a.R.aA                                                                         q.c.aG.m.b.a.R.aG                         q.c.aG.m.b.a.aw.a                                                                         q.c.aG.m.b.a.aw.aA                                                                        q.c.aG.m.b.a.aw.aG                                                                        q.c.aG.m.b.a.aA.a                         q.c.aG.m.b.a.aA.aA                                                                        q.c.aG.m.b.a.aA.aG                                                                        q.c.aG.m.b.a.aG.a                                     q.c.aG.m.b.a.aG.aA                                                                        q.c.aG.m.b.a.aG.aG                                                                        q.c.aG.m.b.b.a.a                                                                          q.c.aG.m.b.b.a.aA                         q.c.aG.m.b.b.a.aG                                                                         q.c.aG.m.b.b.e.a                                                                          q.c.aG.m.b.b.e.aA                                                                         q.c.aG.m.b.b.e.aG                         q.c.aG.m.b.b.m.a                                                                          q.c.aG.m.b.b.m.aA                                                                         q.c.aG.m.b.b.m.aG                                                                         q.c.aG.m.b.b.ao.a                         q.c.aG.m.b.b.o.aA                                                                         q.c.aG.m.b.b.o.aG                                                                         q.c.aG.m.b.b.E.a                                                                          q.c.aG.m.b.b.E.aA                         q.c.aG.m.b.b.E.aG                                                                         q.c.aG.m.b.b.R.a                                                                          q.c.aG.m.b.b.R.aA                                                                         q.c.aG.m.b.b.R.aG                         q.c.aG.m.b.b.aw.a                                                                         q.c.aG.m.b.b.aw.aA                                                                        q.c.aG.m.b.b.aw.aG                                                                        q.c.aG.m.b.b.aA.a                         q.c.aG.m.b.b.aA.aA                                                                        q.c.aG.m.b.b.aA.aG                                                                        q.c.aG.m.b.b.aG.a                                     q.c.aG.m.b.b.aG.aA                                                                        q.c.aG.m.b.b.aG.aG                                                                        q.c.aG.o.a.b.a.a                                                                          q.c.aG.o.a.b.a.aA                         q.c.aG.o.a.b.a.aG                                                                         q.c.aG.o.a.b.e.a                                                                          q.c.aG.o.a.b.e.aA                                                                         q.c.aG.o.a.b.e.aG                         q.c.aG.o.a.b.m.a                                                                          q.c.aG.o.a.b.m.aA                                                                         q.c.aG.o.a.b.m.aG                                                                         q.c.aG.o.a.b.ao.a                         q.c.aG.o.a.b.o.aA                                                                         q.c.aG.o.a.b.o.aG                                                                         q.c.aG.o.a.b.E.a                                                                          q.c.aG.o.a.b.E.aA                         q.c.aG.o.a.b.E.aG                                                                         q.c.aG.o.a.b.R.a                                                                          q.c.aG.o.a.b.R.aA                                                                         q.c.aG.o.a.b.R.aG                         q.c.aG.o.a.b.aw.a                                                                         q.c.aG.o.a.b.aw.aA                                                                        q.c.aG.o.a.b.aw.aG                                                                        q.c.aG.o.a.b.aA.a                         q.c.aG.o.a.b.aA.aA                                                                        q.c.aG.o.a.b.aA.aG                                                                        q.c.aG.o.a.b.aG.a                                     q.c.aG.o.a.b.aG.aA                                                                        q.c.aG.o.a.b.aG.aG                                                                        q.c.aG.o.b.a.a.a                                                                          q.c.aG.o.b.a.a.aA                         q.c.aG.o.b.a.a.aG                                                                         q.c.aG.o.b.a.e.a                                                                          q.c.aG.o.b.a.e.aA                                                                         q.c.aG.o.b.a.e.aG                         q.c.aG.o.b.a.m.a                                                                          q.c.aG.o.b.a.m.aA                                                                         q.c.aG.o.b.a.m.aG                                                                         q.c.aG.o.b.a.ao.a                         q.c.aG.o.b.a.o.aA                                                                         q.c.aG.o.b.a.o.aG                                                                         q.c.aG.o.b.a.E.a                                                                          q.c.aG.o.b.a.E.aA                         q.c.aG.o.b.a.E.aG                                                                         q.c.aG.o.b.a.R.a                                                                          q.c.aG.o.b.a.R.aA                                                                         q.c.aG.o.b.a.R.aG                         q.c.aG.o.b.a.aw.a                                                                         q.c.aG.o.b.a.aw.aA                                                                        q.c.aG.o.b.a.aw.aG                                                                        q.c.aG.o.b.a.aA.a                         q.c.aG.o.b.a.aA.aA                                                                        q.c.aG.o.b.a.aA.aG                                                                        q.c.aG.o.b.a.aG.a                                     q.c.aG.o.b.a.aG.aA                                                                        q.c.aG.o.b.a.aG.aG                                                                        q.c.aG.o.b.b.a.a                                                                          q.c.aG.o.b.b.a.aA                         q.c.aG.o.b.b.a.aG                                                                         q.c.aG.o.b.b.e.a                                                                          q.c.aG.o.b.b.e.aA                                                                         q.c.aG.o.b.b.e.aG                         q.c.aG.o.b.b.m.a                                                                          q.c.aG.o.b.b.m.aA                                                                         q.c.aG.o.b.b.m.aG                                                                         q.c.aG.o.b.b.ao.a                         q.c.aG.o.b.b.o.aA                                                                         q.c.aG.o.b.b.o.aG                                                                         q.c.aG.o.b.b.E.a                                                                          q.c.aG.o.b.b.E.aA                         q.c.aG.o.b.b.E.aG                                                                         q.c.aG.o.b.b.R.a                                                                          q.c.aG.o.b.b.R.aA                                                                         q.c.aG.o.b.b.R.aG                         q.c.aG.o.b.b.aw.a                                                                         q.c.aG.o.b.b.aw.aA                                                                        q.c.aG.o.b.b.aw.aG                                                                        q.c.aG.o.b.b.aA.a                         q.c.aG.o.b.b.aA.aA                                                                        q.c.aG.o.b.b.aA.aG                                                                        q.c.aG.o.b.b.aG.a                                     q.c.aG.o.b.b.aG.aA                                                                        q.c.aG.o.b.b.aG.aG                                                                        q.c.aG.E.a.b.a.a                                                                          q.c.aG.E.a.b.a.aA                         q.c.aG.E.a.b.a.aG                                                                         q.c.aG.E.a.b.e.a                                                                          q.c.aG.E.a.b.e.aA                                                                         q.c.aG.E.a.b.e.aG                         q.c.aG.E.a.b.m.a                                                                          q.c.aG.E.a.b.m.aA                                                                         q.c.aG.E.a.b.m.aG                                                                         q.c.aG.E.a.b.ao.a                         q.c.aG.E.a.b.o.aA                                                                         q.c.aG.E.a.b.o.aG                                                                         q.c.aG.E.a.b.E.a                                                                          q.c.aG.E.a.b.E.aA                         q.c.aG.E.a.b.E.aG                                                                         q.c.aG.E.a.b.R.a                                                                          q.c.aG.E.a.b.R.aA                                                                         q.c.aG.E.a.b.R.aG                         q.c.aG.E.a.b.aw.a                                                                         q.c.aG.E.a.b.aw.aA                                                                        q.c.aG.E.a.b.aw.aG                                                                        q.c.aG.E.a.b.aA.a                         q.c.aG.E.a.b.aA.aA                                                                        q.c.aG.E.a.b.aA.aG                                                                        q.c.aG.E.a.b.aG.a                                     q.c.aG.E.a.b.aG.aA                                                                        q.c.aG.E.a.b.aG.aG                                                                        q.c.aG.E.b.a.a.a                                                                          q.c.aG.E.b.a.a.aA                         q.c.aG.E.b.a.a.aG                                                                         q.c.aG.E.b.a.e.a                                                                          q.c.aG.E.b.a.e.aA                                                                         q.c.aG.E.b.a.e.aG                         q.c.aG.E.b.a.m.a                                                                          q.c.aG.E.b.a.m.aA                                                                         q.c.aG.E.b.a.m.aG                                                                         q.c.aG.E.b.a.ao.a                         q.c.aG.E.b.a.o.aA                                                                         q.c.aG.E.b.a.o.aG                                                                         q.c.aG.E.b.a.E.a                                                                          q.c.aG.E.b.a.E.aA                         q.c.aG.E.b.a.E.aG                                                                         q.c.aG.E.b.a.R.a                                                                          q.c.aG.E.b.a.R.aA                                                                         q.c.aG.E.b.a.R.aG                         q.c.aG.E.b.a.aw.a                                                                         q.c.aG.E.b.a.aw.aA                                                                        q.c.aG.E.b.a.aw.aG                                                                        q.c.aG.E.b.a.aA.a                         q.c.aG.E.b.a.aA.aA                                                                        q.c.aG.E.b.a.aA.aG                                                                        q.c.aG.E.b.a.aG.a                                     q.c.aG.E.b.a.aG.aA                                                                        q.c.aG.E.b.a.aG.aG                                                                        q.c.aG.E.b.b.a.a                                                                          q.c.aG.E.b.b.a.aA                         q.c.aG.E.b.b.a.aG                                                                         q.c.aG.E.b.b.e.a                                                                          q.c.aG.E.b.b.e.aA                                                                         q.c.aG.E.b.b.e.aG                         q.c.aG.E.b.b.m.a                                                                          q.c.aG.E.b.b.m.aA                                                                         q.c.aG.E.b.b.m.aG                                                                         q.c.aG.E.b.b.ao.a                         q.c.aG.E.b.b.o.aA                                                                         q.c.aG.E.b.b.o.aG                                                                         q.c.aG.E.b.b.E.a                                                                          q.c.aG.E.b.b.E.aA                         q.c.aG.E.b.b.E.aG                                                                         q.c.aG.E.b.b.R.a                                                                          q.c.aG.E.b.b.R.aA                                                                         q.c.aG.E.b.b.R.aG                         q.c.aG.E.b.b.aw.a                                                                         q.c.aG.E.b.b.aw.aA                                                                        q.c.aG.E.b.b.aw.aG                                                                        q.c.aG.E.b.b.aA.a                         q.c.aG.E.b.b.aA.aA                                                                        q.c.aG.E.b.b.aA.aG                                                                        q.c.aG.E.b.b.aG.a                                     q.c.aG.E.b.b.aG.aA                                                                        q.c.aG.E.b.b.aG.aG                                                                        q.c.aG.R.a.b.a.a                                                                          q.c.aG.R.a.b.a.aA                         q.c.aG.R.a.b.a.aG                                                                         q.c.aG.R.a.b.e.a                                                                          q.c.aG.R.a.b.e.aA                                                                         q.c.aG.R.a.b.e.aG                         q.c.aG.R.a.b.m.a                                                                          q.c.aG.R.a.b.m.aA                                                                         q.c.aG.R.a.b.m.aG                                                                         q.c.aG.R.a.b.ao.a                         q.c.aG.R.a.b.o.aA                                                                         q.c.aG.R.a.b.o.aG                                                                         q.c.aG.R.a.b.E.a                                                                          q.c.aG.R.a.b.E.aA                         q.c.aG.R.a.b.E.aG                                                                         q.c.aG.R.a.b.R.a                                                                          q.c.aG.R.a.b.R.aA                                                                         q.c.aG.R.a.b.R.aG                         q.c.aG.R.a.b.aw.a                                                                         q.c.aG.R.a.b.aw.aA                                                                        q.c.aG.R.a.b.aw.aG                                                                        q.c.aG.R.a.b.aA.a                         q.c.aG.R.a.b.aA.aA                                                                        q.c.aG.R.a.b.aA.aG                                                                        q.c.aG.R.a.b.aG.a                                     q.c.aG.R.a.b.aG.aA                                                                        q.c.aG.R.a.b.aG.aG                                                                        q.c.aG.R.b.a.a.a                                                                          q.c.aG.R.b.a.a.aA                         q.c.aG.R.b.a.a.aG                                                                         q.c.aG.R.b.a.e.a                                                                          q.c.aG.R.b.a.e.aA                                                                         q.c.aG.R.b.a.e.aG                         q.c.aG.R.b.a.m.a                                                                          q.c.aG.R.b.a.m.aA                                                                         q.c.aG.R.b.a.m.aG                                                                         q.c.aG.R.b.a.ao.a                         q.c.aG.R.b.a.o.aA                                                                         q.c.aG.R.b.a.o.aG                                                                         q.c.aG.R.b.a.E.a                                                                          q.c.aG.R.b.a.E.aA                         q.c.aG.R.b.a.E.aG                                                                         q.c.aG.R.b.a.R.a                                                                          q.c.aG.R.b.a.R.aA                                                                         q.c.aG.R.b.a.R.aG                         q.c.aG.R.b.a.aw.a                                                                         q.c.aG.R.b.a.aw.aA                                                                        q.c.aG.R.b.a.aw.aG                                                                        q.c.aG.R.b.a.aA.a                         q.c.aG.R.b.a.aA.aA                                                                        q.c.aG.R.b.a.aA.aG                                                                        q.c.aG.R.b.a.aG.a                                     q.c.aG.R.b.a.aG.aA                                                                        q.c.aG.R.b.a.aG.aG                                                                        q.c.aG.R.b.b.a.a                                                                          q.c.aG.R.b.b.a.aA                         q.c.aG.R.b.b.a.aG                                                                         q.c.aG.R.b.b.e.a                                                                          q.c.aG.R.b.b.e.aA                                                                         q.c.aG.R.b.b.e.aG                         q.c.aG.R.b.b.m.a                                                                          q.c.aG.R.b.b.m.aA                                                                         q.c.aG.R.b.b.m.aG                                                                         q.c.aG.R.b.b.ao.a                         q.c.aG.R.b.b.o.aA                                                                         q.c.aG.R.b.b.o.aG                                                                         q.c.aG.R.b.b.E.a                                                                          q.c.aG.R.b.b.E.aA                         q.c.aG.R.b.b.E.aG                                                                         q.c.aG.R.b.b.R.a                                                                          q.c.aG.R.b.b.R.aA                                                                         q.c.aG.R.b.b.R.aG                         q.c.aG.R.b.b.aw.a                                                                         q.c.aG.R.b.b.aw.aA                                                                        q.c.aG.R.b.b.aw.aG                                                                        q.c.aG.R.b.b.aA.a                         q.c.aG.R.b.b.aA.aA                                                                        q.c.aG.R.b.b.aA.aG                                                                        q.c.aG.R.b.b.aG.a                                     q.c.aG.R.b.b.aG.aA                                                                        q.c.aG.R.b.b.aG.aG                                                                        q.c.aG.aw.a.b.a.a                                     q.c.aG.aw.a.b.a.aA                                                                        q.c.aG.aw.a.b.a.aG                                                                        q.c.aG.aw.a.b.e.a                                     q.c.aG.aw.a.b.e.aA                                                                        q.c.aG.aw.a.b.e.aG                                                                        q.c.aG.aw.a.b.m.a                                     q.c.aG.aw.a.b.m.aA                                                                        q.c.aG.aw.a.b.m.aG                                                                        q.c.aG.aw.a.b.ao.a                                    q.c.aG.aw.a.b.o.aA                                                                        q.c.aG.aw.a.b.o.aG                                                                        q.c.aG.aw.a.b.E.a                                     q.c.aG.aw.a.b.E.aA                                                                        q.c.aG.aw.a.b.E.aG                                                                        q.c.aG.aw.a.b.R.a                                     q.c.aG.aw.a.b.R.aA                                                                        q.c.aG.aw.a.b.R.aG                                                                        q.c.aG.aw.a.b.aw.a                                    q.c.aG.aw.a.b.aw.aA     q.c.aG.aw.a.b.aw.aG                                   q.c.aG.aw.a.b.aA.a                                                                        q.c.aG.aw.a.b.aA.aA                                               q.c.aG.aw.a.b.aA.aG     q.c.aG.aw.a.b.aG.a                                    q.c.aG.aw.a.b.aG.aA     q.c.aG.aw.a.b.aG.aG                                                                       q.c.aG.aw.b.a.a.a                         q.c.aG.aw.b.a.a.aA                                                                        q.c.aG.aw.b.a.a.aG                                                                        q.c.aG.aw.b.a.e.a                                     q.c.aG.aw.b.a.e.aA                                                                        q.c.aG.aw.b.a.e.aG                                                                        q.c.aG.aw.b.a.m.a                                     q.c.aG.aw.b.a.m.aA                                                                        q.c.aG.aw.b.a.m.aG                                                                        q.c.aG.aw.b.a.ao.a                                    q.c.aG.aw.b.a.o.aA                                                                        q.c.aG.aw.b.a.o.aG                                                                        q.c.aG.aw.b.a.E.a                                     q.c.aG.aw.b.a.E.aA                                                                        q.c.aG.aw.b.a.E.aG                                                                        q.c.aG.aw.b.a.R.a                                     q.c.aG.aw.b.a.R.aA                                                                        q.c.aG.aw.b.a.R.aG                                                                        q.c.aG.aw.b.a.aw.a                                    q.c.aG.aw.b.a.aw.aA     q.c.aG.aw.b.a.aw.aG                                   q.c.aG.aw.b.a.aA.a                                                                        q.c.aG.aw.b.a.aA.aA                                               q.c.aG.aw.b.a.aA.aG     q.c.aG.aw.b.a.aG.a                                    q.c.aG.aw.b.a.aG.aA     q.c.aG.aw.b.a.aG.aG                                                                       q.c.aG.aw.b.b.a.a                         q.c.aG.aw.b.b.a.aA                                                                        q.c.aG.aw.b.b.a.aG                                                                        q.c.aG.aw.b.b.e.a                                     q.c.aG.aw.b.b.e.aA                                                                        q.c.aG.aw.b.b.e.aG                                                                        q.c.aG.aw.b.b.m.a                                     q.c.aG.aw.b.b.m.aA                                                                        q.c.aG.aw.b.b.m.aG                                                                        q.c.aG.aw.b.b.ao.a                                    q.c.aG.aw.b.b.o.aA                                                                        q.c.aG.aw.b.b.o.aG                                                                        q.c.aG.aw.b.b.E.a                                     q.c.aG.aw.b.b.E.aA                                                                        q.c.aG.aw.b.b.E.aG                                                                        q.c.aG.aw.b.b.R.a                                     q.c.aG.aw.b.b.R.aA                                                                        q.c.aG.aw.b.b.R.aG                                                                        q.c.aG.aw.b.b.aw.a                                    q.c.aG.aw.b.b.aw.aA     q.c.aG.aw.b.b.aw.aG                                   q.c.aG.aw.b.b.aA.a                                                                        q.c.aG.aw.b.b.aA.aA                                               q.c.aG.aw.b.b.aA.aG     q.c.aG.aw.b.b.aG.a                                    q.c.aG.aw.b.b.aG.aA     q.c.aG.aw.b.b.aG.aG                                                                       q.c.aG.aA.a.b.a.a                         q.c.aG.aA.a.b.a.aA                                                                        q.c.aG.aA.a.b.a.aG                                                                        q.c.aG.aA.a.b.e.a                                     q.c.aG.aA.a.b.e.aA                                                                        q.c.aG.aA.a.b.e.aG                                                                        q.c.aG.aA.a.b.m.a                                     q.c.aG.aA.a.b.m.aA                                                                        q.c.aG.aA.a.b.m.aG                                                                        q.c.aG.aA.a.b.ao.a                                    q.c.aG.aA.a.b.o.aA                                                                        q.c.aG.aA.a.b.o.aG                                                                        q.c.aG.aA.a.b.E.a                                     q.c.aG.aA.a.b.E.aA                                                                        q.c.aG.aA.a.b.E.aG                                                                        q.c.aG.aA.a.b.R.a                                     q.c.aG.aA.a.b.R.aA                                                                        q.c.aG.aA.a.b.R.aG                                                                        q.c.aG.aA.a.b.aw.a                                    q.c.aG.aA.a.b.aw.aA     q.c.aG.aA.a.b.aw.aG                                   q.c.aG.aA.a.b.aA.a                                                                        q.c.aG.aA.a.b.aA.aA                                               q.c.aG.aA.a.b.aA.aG     q.c.aG.aA.a.b.aG.a                                    q.c.aG.aA.a.b.aG.aA     q.c.aG.aA.a.b.aG.aG                                                                       q.c.aG.aA.b.a.a.a                         q.c.aG.aA.b.a.a.a                                                             q.c.aG.aA.b.a.a.aA                                                                        q.c.aG.aA.b.a.a.aG                                                                        q.c.aG.aA.a.b.e.a                                     q.c.aG.aA.a.b.e.aA                                                                        q.c.aG.aA.a.b.e.aG                                                                        q.c.aG.aA.a.b.m.a                                     q.c.aG.aA.a.b.m.aA                                                                        q.c.aG.aA.a.b.m.aG                                                                        q.c.aG.aA.a.b.ao.a                                    q.c.aG.aA.a.b.o.aA                                                                        q.c.aG.aA.a.b.o.aG                                                                        q.c.aG.aA.a.b.E.a                                     q.c.aG.aA.a.b.E.aA                                                                        q.c.aG.aA.a.b.E.aG                                                                        q.c.aG.aA.a.b.R.a                                     q.c.aG.aA.a.b.R.aA                                                                        q.c.aG.aA.a.b.R.aG                                                                        q.c.aG.aA.a.b.aw.a                                    q.c.aG.aA.a.b.aw.aA     q.c.aG.aA.a.b.aw.aG                                   q.c.aG.aA.a.b.aA.a                                                                        q.c.aG.aA.a.b.aA.aA                                               q.c.aG.aA.a.b.aA.aG     q.c.aG.aA.a.b.aG.a                                    q.c.aG.aA.a.b.aG.aA     q.c.aG.aA.a.b.aG.aG                                                                       q.c.aG.aA.b.b.a.a                         q.c.aG.aA.b.b.a.aA                                                                        q.c.aG.aA.b.b.a.aG                                                                        q.c.aG.aA.b.b.e.a                                     q.c.aG.aA.b.b.e.aA                                                                        q.c.aG.aA.b.b.e.aG                                                                        q.c.aG.aA.b.b.m.a                                     q.c.aG.aA.b.b.m.aA                                                                        q.c.aG.aA.b.b.m.aG                                                                        q.c.aG.aA.b.b.ao.a                                    q.c.aG.aA.b.b.o.aA                                                                        q.c.aG.aA.b.b.o.aG                                                                        q.c.aG.aA.b.b.E.a                                     q.c.aG.aA.b.b.E.aA                                                                        q.c.aG.aA.b.b.E.aG                                                                        q.c.aG.aA.b.b.R.a                                     q.c.aG.aA.b.b.R.aA                                                                        q.c.aG.aA.b.b.R.aG                                                                        q.c.aG.aA.b.b.aw.a                                    q.c.aG.aA.b.b.aw.aA     q.c.aG.aA.b.b.aw.aG                                   q.c.aG.aA.b.b.aA.a                                                                        q.c.aG.aA.b.b.aA.aA                                               q.c.aG.aA.b.b.aA.aG     q.c.aG.aA.b.b.aG.a                                    q.c.aG.aA.b.b.aG.aA     q.c.aG.aA.b.b.aG.aG                                                                       q.c.aG.aG.a.b.a.a                         q.c.aG.aG.a.b.a.aA                                                                        q.c.aG.aG.a.b.a.aG                                                                        q.c.aG.aG.a.b.e.a                                     q.c.aG.aG.a.b.e.aA                                                                        q.c.aG.aG.a.b.e.aG                                                                        q.c.aG.aG.a.b.m.a                                     q.c.aG.aG.a.b.m.aA                                                                        q.c.aG.aG.a.b.m.aG                                                                        q.c.aG.aG.a.b.ao.a                                    q.c.aG.aG.a.b.o.aA                                                                        q.c.aG.aG.a.b.o.aG                                                                        q.c.aG.aG.a.b.E.a                                     q.c.aG.aG.a.b.E.aA                                                                        q.c.aG.aG.a.b.E.aG                                                                        q.c.aG.aG.a.b.R.a                                     q.c.aG.aG.a.b.R.aA                                                                        q.c.aG.aG.a.b.R.aG                                                                        q.c.aG.aG.a.b.aw.a                                    q.c.aG.aG.a.b.aw.aA     q.c.aG.aG.a.b.aw.aG                                   q.c.aG.aG.a.b.aA.a                                                                        q.c.aG.aG.a.b.aA.aA                                               q.c.aG.aG.a.b.aA.aG     q.c.aG.aG.a.b.aG.a                                    q.c.aG.aG.a.b.aG.aA     q.c.aG.aG.a.b.aG.aG                                                                       q.c.aG.aG.b.a.a.a                         q.c.aG.aG.b.a.a.aA                                                                        q.c.aG.aG.b.a.a.aG                                                                        q.c.aG.aG.b.a.e.a                                                                         q.c.aG.aG.b.a.e.aA                        q.c.aG.aG.b.a.e.aG                                                                        q.c.aG.aG.b.a.m.a                                                                         q.c.aG.aG.b.a.m.aA                                    q.c.aG.aG.b.a.m.aG                                                                        q.c.aG.aG.b.a.ao.a                                                                        q.c.aG.aG.b.a.o.aA                                                                        q.c.aG.aG.b.a.o.aG                        q.c.aG.aG.b.a.E.a                                                                         q.c.aG.aG.b.a.E.aA                                                                        q.c.aG.aG.b.a.E.aG                                                                        q.c.aG.aG.b.a.R.a                         q.c.aG.aG.b.a.R.aA                                                                        q.c.aG.aG.b.a.R.aG                                                                        q.c.aG.aG.b.a.aw.a                                    q.c.aG.aG.b.a.aw.aA     q.c.aG.aG.b.a.aw.aG                                   q.c.aG.aG.b.a.aA.a                                                                        q.c.aG.aG.b.a.aA.aA                                               q.c.aG.aG.b.a.aA.aG     q.c.aG.aG.b.a.aG.a                                    q.c.aG.aG.b.a.aG.aA     q.c.aG.aG.b.a.aG.aG                                                                       q.c.aG.aG.b.b.a.a                         q.c.aG.aG.b.b.a.aA                                                                        q.c.aG.aG.b.b.a.aG                                                                        q.c.aG.aG.b.b.e.a                                                                         q.c.aG.aG.b.b.e.aA                        q.c.aG.aG.b.b.e.aG                                                                        q.c.aG.aG.b.b.m.a                                                                         q.c.aG.aG.b.b.m.aA                                    q.c.aG.aG.b.b.m.aG                                                                        q.c.aG.aG.b.b.ao.a                                                                        q.c.aG.aG.b.b.o.aA                                                                        q.c.aG.aG.b.b.o.aG                        q.c.aG.aG.b.b.E.a                                                                         q.c.aG.aG.b.b.E.aA                                                                        q.c.aG.aG.b.b.E.aG                                                                        q.c.aG.aG.b.b.R.a                         q.c.aG.aG.b.b.R.aA                                                                        q.c.aG.aG.b.b.R.aG                                                                        q.c.aG.aG.b.b.aw.a                                    q.c.aG.aG.b.b.aw.aA     q.c.aG.aG.b.b.aw.aG                                   q.c.aG.aG.b.b.aA.a                                                                        q.c.aG.aG.b.b.aA.aA                                               q.c.aG.aG.b.b.aA.aG     q.c.aG.aG.b.b.aG.a                                    q.c.aG.aG.b.b.aG.aA     q.c.aG.aG.b.b.aG.aG                                   k.c.aN.o.a.b.a.a                                                                          k.c.aN.o.a.b.a.aA                                                                         k.c.aN.o.a.b.a.aG                                                                         k.c.aN.o.a.b.e.a                          k.c.aN.o.a.b.e.aA                                                                         k.c.aN.o.a.b.e.aG                                                                         k.c.aN.o.a.b.m.a.                                     k.c.aN.o.a.b.m.aA                                                                         k.c.aN.o.a.b.m.aG                                                                         k.c.aN.o.b.a.a.a                                                                          k.c.aN.o.b.a.a.aA                         k.c.aN.o.b.a.a.aG                                                                         k.c.aN.o.b.a.e.a                                                                          k.c.aN.o.b.a.e.aA                                                                         k.c.aN.o.b.a.e.aG                         k.c.aN.o.b.a.m.a                                                                          k.c.aN.o.b.a.m.aA                                                                         k.c.aN.o.b.a.m.aG                                                                         k.c.aN.o.b.b.a.a                          k.c.aN.o.b.b.a.aA                                                                         k.c.aN.o.b.b.a.aG                                                                         k.c.aN.o.b.b.e.a                                                                          k.c.aN.o.b.b.e.aA                         k.c.aN.o.b.b.e.aG                                                                         k.c.aN.o.b.b.m.a                                                                          k.c.aN.o.b.b.m.aA                                     k.c.aN.o.b.b.m.aG                                                                         k.c.aN.q.a.b.a.a                                                                          k.c.aN.q.a.b.a.aA                                                                         k.c.aN.q.a.b.a.aG                         k.c.aN.q.a.b.e.a                                                                          k.c.aN.q.a.b.e.aA                                                                         k.c.aN.q.a.b.e.aG                                                                         k.c.aN.q.a.b.m.a                          k.c.aN.q.a.b.m.aA                                                                         k.c.aN.q.a.b.m.aG                                                                         k.c.aN.q.b.a.a.a                                                                          k.c.aN.q.b.a.a.aA                         k.c.aN.q.b.a.a.aG                                                                         k.c.aN.q.b.a.e.a                                                                          k.c.aN.q.b.a.e.aA                                                                         k.c.aN.q.b.a.e.aG                         k.c.aN.q.b.a.m.a                                                                          k.c.aN.q.b.a.m.aA                                                                         k.c.aN.q.b.a.m.aG                                                                         k.c.aN.q.b.b.a.a                          k.c.aN.q.b.b.a.aA                                                                         k.c.aN.q.b.b.a.aG                                                                         k.c.aN.q.b.b.e.a                                                                          k.c.aN.q.b.b.e.aA                         k.c.aN.q.b.b.e.aG                                                                         k.c.aN.q.b.b.m.a                                                                          k.c.aN.q.b.b.m.aA                                     k.c.aN.q.b.b.m.aG                                                                         q.c.aN.o.a.b.a.a                                                                          q.c.aN.o.a.b.a.aA                                                                         q.c.aN.o.a.b.a.aG                         q.c.aN.o.a.b.e.a                                                                          q.c.aN.o.a.b.e.aA                                                                         q.c.aN.o.a.b.e.aG                                                                         q.c.aN.o.a.b.m.a                          q.c.aN.o.a.b.m.aA                                                                         q.c.aN.o.a.b.m.aG                                                                         q.c.aN.o.b.a.a.a                                                                          q.c.aN.o.b.a.a.aA                         q.c.aN.o.b.a.a.aG                                                                         q.c.aN.o.b.a.e.a                                                                          q.c.aN.o.b.a.e.aA                                                                         q.c.aN.o.b.a.e.aG                         q.c.aN.o.b.a.m.a                                                                          q.c.aN.o.b.a.m.aA                                                                         q.c.aN.o.b.a.m.aG                                                                         q.c.aN.o.b.b.a.a                          q.c.aN.o.b.b.a.aA                                                                         q.c.aN.o.b.b.a.aG                                                                         q.c.aN.o.b.b.e.a                                                                          q.c.aN.o.b.b.e.aA                         q.c.aN.o.b.b.e.aG                                                                         q.c.aN.o.b.b.m.a                                                                          q.c.aN.o.b.b.m.aA                                     q.c.aN.o.b.b.m.aG                                                                         q.c.aN.q.a.b.a.a                                                                          q.c.aN.q.a.b.a.aA                                                                         q.c.aN.q.a.b.a.aG                         q.c.aN.q.a.b.e.a                                                                          q.c.aN.q.a.b.e.aA                                                                         q.c.aN.q.a.b.e.aG                                                                         q.c.aN.q.a.b.m.a                          q.c.aN.q.a.b.m.aA                                                                         q.c.aN.q.a.b.m.aG                                                                         q.c.aN.q.b.a.a.a                                                                          q.c.aN.q.b.a.a.aA                         q.c.aN.q.b.a.a.aG                                                                         q.c.aN.q.b.a.e.a                                                                          q.c.aN.q.b.a.e.aA                                                                         q.c.aN.q.b.a.e.aG                         q.c.aN.q.b.a.m.a                                                                          q.c.aN.q.b.a.m.aA                                                                         q.c.aN.q.b.a.m.aG                                                                         q.c.aN.q.a.b.a.a                          q.c.aN.q.a.b.a.aA                                                                         q.c.aN.q.a.b.a.aG                                                                         q.c.aN.q.a.b.e.a                                                                          q.c.aN.q.a.b.e.aA                         q.c.aN.q.a.b.e.aG                                                                         q.c.aN.q.a.b.m.a                                                                          q.c.aN.q.a.b.m.aA                                                                         q.c.aN.q.a.b.m.aG                         k.c.a.a.a.b.o.aN                                                                          k.c.a.a.a.b.q.aN                                                                          k.c.a.a.b.a.o.aN                                                                          k.c.a.a.b.a.q.aN                          k.c.a.a.b.b.o.aN                                                                          k.c.a.a.b.b.q.aN                                                                          k.c.a.e.a.b.o.aN                                                                          k.c.a.e.a.b.q.aN                          k.c.a.e.b.a.o.aN                                                                          k.c.a.e.b.a.q.aN                                                                          k.c.a.e.b.b.o.aN                                                                          k.c.a.e.b.b.q.aN                          k.c.a.m.a.b.o.aN                                                                          k.c.a.m.a.b.q.aN                                                                          k.c.a.m.b.a.o.aN                                                                          k.c.a.m.b.a.q.aN                          k.c.a.m.b.b.o.aN                                                                          k.c.a.m.b.b.q.aN                                                                          k.c.aA.a.a.b.o.aN                                     k.c.aA.a.a.b.q.aN                                                                         k.c.aA.a.b.a.o.aN                                                                         k.c.aA.a.b.a.q.aN                                     k.c.aA.a.b.b.o.aN                                                                         k.c.aA.a.b.b.q.aN                                                                         k.c.aA.e.b.a.o.aN                                     k.c.aA.e.a.b.q.aN                                                                         k.c.aA.e.a.b.o.aN                                                                         k.c.aA.m.a.b.q.aN                                     k.c.aA.m.a.b.o.aN                                                                         k.c.aA.m.b.a.q.aN                                                                         k.c.aA.m.b.a.o.aN                                     k.c.aA.m.b.b.q.aN                                                                         k.c.aA.m.b.a.o.aN                                                                         k.c.aA.m.b.a.q.aN                                     k.c.aA.m.b.b.o.aN                                                                         k.c.aA.m.b.b.q.aN                                                                         k.c.aG.a.a.b.o.aN                                     k.c.aG.a.a.b.q.aN                                                                         k.c.aG.a.b.a.o.aN                                                                         k.c.aG.a.b.a.q.aN                                     k.c.aG.a.b.b.o.aN                                                                         k.c.aG.a.b.b.q.aN                                                                         k.c.aG.e.a.b.o.aN                                     k.c.aG.e.a.b.q.aN                                                                         k.c.aG.e.b.a.o.aN                                                                         k.c.aG.e.b.a.q.aN                                     k.c.aG.e.b.b.o.aN                                                                         k.c.aG.e.b.b.q.aN                                                                         k.c.aG.m.a.b.o.aN                                     k.c.aG.m.a.b.q.aN                                                                         k.c.aG.m.b.a.o.aN        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            q.c.a.e.b.a.q.aN                          q.c.a.e.b.b.o.aN                                                                          q.c.a.e.b.b.q.aN                                                                          q.c.a.m.a.b.o.aN                                                                          q.c.a.m.a.b.q.aN                          q.c.a.m.b.a.o.aN                                                                          q.c.a.m.b.a.q.aN                                                                          q.c.a.m.b.b.o.aN                                                                          q.c.a.m.b.b.q.aN                          q.c.aA.a.a.b.o.aN                                                                         q.c.aA.a.a.b.q.aN                                                                         q.c.aA.a.b.a.o.aN                                     q.c.aA.a.b.a.q.aN                                                                        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q.c.a.jA.b.b.ak.a                                                                         q.c.a.kB.b.b.ak.a                         q.c.a.kC.b.b.ak.a                                                                         q.c.a.kL.b.b.ak.a                                                                         q.c.a.kM.b.b.ak.a                                                                         q.c.a.kN.b.b.ak.a                         q.c.a.kO.b.b.ak.a                                                                         q.c.a.kP.b.b.ak.a                                                                         q.c.a.kQ.b.b.ak.a                                                                         k.c.a.aT.b.b.ao.a                         k.c.a.aU.b.b.ao.a                                                                         k.c.a.bB.b.b.ao.a                                                                         k.c.a.bF.b.b.ao.a                                                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  k.c.a.fK.b.b.ao.a                                                                         k.c.a.fP.b.b.ao.a                                                                         k.c.a.fR.b.b.ao.a                                                                         k.c.a.jA.b.b.ao.a                         k.c.a.kB.b.b.ao.a                                                                         k.c.a.kC.b.b.ao.a                                                                         k.c.a.kL.b.b.ao.a                                                                         k.c.a.kM.b.b.ao.a                         k.c.a.kN.b.b.ao.a                                                                         k.c.a.kO.b.b.ao.a                                                                         k.c.a.kP.b.b.ao.a                                                                         k.c.a.kQ.b.b.ao.a                         q.c.a.aT.b.b.ao.a                                                                         q.c.a.aU.b.b.ao.a                                                                         q.c.a.bB.b.b.ao.a                                                                         q.c.a.bF.b.b.ao.a                         q.c.a.bG.b.b.ao.a                                                                         q.c.a.cE.b.b.ao.a                                                                         q.c.a.cG.b.b.ao.a                                                                         q.c.a.cH.b.b.ao.a                         q.c.a.cJ.b.b.b.a                                                                          q.c.a.cL.b.b.ao.a                                                                         q.c.a.cN.b.b.ao.a                                                                         q.c.a.cS.b.b.ao.a                         q.c.a.cU.b.b.ao.a                                                                         q.c.a.cY.b.b.ao.a                                                                         q.c.a.dB.b.b.ao.a                                                                         q.c.a.dD.b.b.ao.a                         q.c.a.fF.b.b.ao.a                                                                         q.c.a.fK.b.b.ao.a                                                                         q.c.a.fP.b.b.ao.a                                                                         q.c.a.fR.b.b.ao.a                         q.c.a.jA.b.b.ao.a                                                                         q.c.a.kB.b.b.ao.a                                                                         q.c.a.kC.b.b.ao.a                                                                         q.c.a.kL.b.b.ao.a                         q.c.a.kM.b.b.ao.a                                                                         q.c.a.kN.b.b.ao.a                                                                         q.c.a.kO.b.b.ao.a                                                                         q.c.a.kP.b.b.ao.a                         q.c.a.kQ.b.b.ao.a                                                                         k.c.a.aT.b.b.aw.a                                                                         k.c.a.aU.b.b.aw.a                                                                         k.c.a.bB.b.b.aw.a                         k.c.a.bF.b.b.aw.a                                                                         k.c.a.bG.b.b.aw.a                                                                         k.c.a.cE.b.b.aw.a                                                                         k.c.a.cG.b.b.aw.a                         k.c.a.cH.b.b.aw.a                                                                         k.c.a.cJ.b.b.b.a                                                                          k.c.a.cL.b.b.aw.a                                                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              k.c.a.kL.b.b.aw.a                                                                         k.c.a.kM.b.b.aw.a                                     k.c.a.kN.b.b.aw.a                                                                         k.c.a.kO.b.b.aw.a                                                                         k.c.a.kP.b.b.aw.a                                     k.c.a.kQ.b.b.aw.a                                                                         q.c.a.aT.b.b.aw.a                                                                         q.c.a.aU.b.b.aw.a                                                                         q.c.a.bB.b.b.aw.a                         q.c.a.bF.b.b.aw.a                                                                         q.c.a.bG.b.b.aw.a                                                                         q.c.a.cE.b.b.aw.a                                                                         q.c.a.cG.b.b.aw.a                         q.c.a.cH.b.b.aw.a                                                                         q.c.a.cJ.b.b.b.a                                                                          q.c.a.cL.b.b.aw.a                                                                         q.c.a.cN.b.b.aw.a                         q.c.a.cS.b.b.aw.a                                                                         q.c.a.cU.b.b.aw.a                                                                         q.c.a.cYb.b.aw.a                                                                          q.c.a.dB.b.b.aw.a                         q.c.a.dD.b.b.aw.a                                                                         q.c.a.fF.b.b.aw.a                                                                         q.c.a.fK.b.b.aw.a                                                                         q.c.a.fP.b.b.aw.a                         q.c.a.fR.b.b.aw.a                                                                         q.c.a.jA.b.b.aw.a                                                                         q.c.a.kB.b.b.aw.a                                                                         q.c.a.kC.b.b.aw.a                         q.c.a.kL.b.b.aw.a                                                                         q.c.a.kM.b.b.aw.a                                                                         q.c.a.kN.b.b.aw.a                                     q.c.a.kO.b.b.aw.a                                                                         q.c.a.kP.b.b.aw.a                                                                         q.c.a.kQ.b.b.aw.a                                                                         k.c.a.aU.b.b.aT.a                         k.c.a.bB.b.b.aT.a                                                                         k.c.a.bF.b.b.aT.a                                                                         k.c.a.bG.b.b.aT.a                                                                         k.c.a.cE.b.b.aT.a                         k.c.a.cG.b.b.aT.a                                                                         k.c.a.cH.b.b.aT.a                                                                         k.c.a.cJ.b.b.b.a                                                                          k.c.a.cL.b.b.aT.a                         k.c.a.cN.b.b.aT.a                                                                         k.c.a.cS.b.b.aT.a                                                                         k.c.a.cU.b.b.aT.a                                                                         k.c.a.cY.b.b.aT.a                         k.c.a.dB.b.b.aT.a                                                                         k.c.a.dD.b.b.aT.a                                                                         k.c.a.fF.b.b.aT.a                                                                         k.c.a.fK.b.b.aT.a                         k.c.a.fP.b.b.aT.a                                                                         k.c.a.fR.b.b.aT.a                                                                         k.c.a.jA.b.b.aT.a                                                                         k.c.a.kB.b.b.aT.a                         k.c.a.kC.b.b.aT.a                                                                         k.c.a.kL.b.b.aT.a                                                                         k.c.a.kM.b.b.aT.a                                                                         k.c.a.kN.b.b.aT.a                         k.c.a.kO.b.b.aT.a                                                                         k.c.a.kP.b.b.aT.a                                                                         k.c.a.kQ.b.b.aT.a                                                                         q.c.a.aU.b.b.aT.a                         q.c.a.bB.b.b.aT.a                                                                         q.c.a.bF.b.b.aT.a                                                                         q.c.a.bG.b.b.aT.a                                                                         q.c.a.cE.b.b.aT.a                         q.c.a.cG.b.b.aT.a                                                                         q.c.a.cH.b.b.aT.a                                                                         q.c.a.cJ.b.b.b.a                                                                          q.c.a.cL.b.b.aT.a                         q.c.a.cN.b.b.aT.a                                                                         q.c.a.cS.b.b.aT.a                                                                         q.c.a.cU.b.b.aT.a                                                                         q.c.a.cY.b.b.aT.a                         q.c.a.dB.b.b.aT.a                                                                         q.c.a.dD.b.b.aT.a                                                                         q.c.a.fF.b.b.aT.a                                                                         q.c.a.fK.b.b.aT.a                         q.c.a.fP.b.b.aT.a                                                                         q.c.a.fR.b.b.aT.a                                                                         q.c.a.jA.b.b.aT.a                                                                         q.c.a.kB.b.b.aT.a                         q.c.a.kC.b.b.aT.a                                                                         q.c.a.kL.b.b.aT.a                                                                         q.c.a.kM.b.b.aT.a                                                                         q.c.a.kN.b.b.aT.a                         q.c.a.kO.b.b.aT.a                                                                         q.c.a.kP.b.b.aT.a                                                                         q.c.a.kQ.b.b.aT.a                                                                         k.c.a.aT.b.b.aU.a                         k.c.a.bB.b.b.aU.a                                                                         k.c.a.bF.b.b.aU.a                                                                         k.c.a.bG.b.b.aU.a                                                                         k.c.a.cE.b.b.aU.a                         k.c.a.cG.b.b.aU.a                                                                         k.c.a.cH.b.b.aU.a                                                                         k.c.a.cJ.b.b.b.a                                                                          k.c.a.cL.b.b.aU.a                         k.c.a.cN.b.b.aU.a                                                                         k.c.a.cS.b.b.aU.a                                                                         k.c.a.cU.b.b.aU.a                                                                         k.c.a.cY.b.b.aU.a                         k.c.a.dB.b.b.aU.a                                                                         k.c.a.dD.b.b.aU.a                                                                         k.c.a.fF.b.b.aU.a                                                                         k.c.a.fK.b.b.aU.a                         k.c.a.fP.b.b.aU.a                                                                         k.c.a.fR.b.b.aU.a                                                                         k.c.a.jA.b.b.aU.a                                                                         k.c.a.kB.b.b.aU.a                         k.c.a.kC.b.b.aU.a                                                                         k.c.a.kL.b.b.aU.a                                                                         k.c.a.kM.b.b.aU.a                                     k.c.a.kN.b.b.aU.a                                                                         k.c.a.kO.b.b.aU.a                                                                         k.c.a.kP.b.b.aU.a                                     k.c.a.kQ.b.b.aU.a                                                                         q.c.a.aT.b.b.aU.a                                                                         q.c.a.bB.b.b.aU.a                                                                         q.c.a.bF.b.b.aU.a                         q.c.a.bG.b.b.aU.a                                                                         q.c.a.cE.b.b.aU.a                                                                         q.c.a.cG.b.b.aU.a                                                                         q.c.a.cH.b.b.aU.a                         q.c.a.cJ.b.b.b.a                                                                          q.c.a.cL.b.b.aU.a                                                                         q.c.a.cN.b.b.aU.a                                                                         q.c.a.cS.b.b.aU.a                         q.c.a.cU.b.b.aU.a                                                                         q.c.a.cY.b.b.aU.a                                                                         q.c.a.dB.b.b.aU.a                                                                         q.c.a.dD.b.b.aU.a                         q.c.a.fF.b.b.aU.a                                                                         q.c.a.fK.b.b.aU.a                                                                         q.c.a.fP.b.b.aU.a                                                                         q.c.a.fR.b.b.aU.a                         q.c.a.jA.b.b.aU.a                                                                         q.c.a.kB.b.b.aU.a                                                                         q.c.a.kC.b.b.aU.a                                                                         q.c.a.kL.b.b.aU.a                         q.c.a.kM.b.b.aU.a                                                                         q.c.a.kN.b.b.aU.a                                                                         q.c.a.kO.b.b.aU.a                                                                         q.c.a.kP.b.b.aU.a                         q.c.a.kQ.b.b.aU.a                                                                         K.c.a.a.b.b.a.a                                                                           K.c.a.a.b.b.a.aA                                                                          K.c.a.a.b.b.m.a                           K.c.a.a.b.b.m.aA                                                                          K.c.a.a.b.b.ak.a                                                                          K.c.a.ab.b.ak.aA                                                                          K.c.a.a.b.b.cP.a                          K.c.a.a.b.b.cP.aA                                                                         K.c.a.a.b.b.cS.a                                                                          K.c.a.a.b.b.cS.aA                                                                         K.c.a.a.b.b.cT.a                          K.c.a.a.b.b.cT.aA                                                                         K.c.a.a.b.b.kr.a                                                                          K.c.a.a.b.b.kr.aA                                                                         K.c.a.m.b.b.a.a                           K.c.a.m.b.b.a.aA                                                                          K.c.a.m.b.b.m.a                                                                           K.c.a.m.b.b.m.aA                                                                          K.c.a.m.b.b.ak.a                          K.c.a.m.b.b.ak.aA                                                                         K.c.a.m.b.b.cP.a                                                                          K.c.a.m.b.b.cP.aA                                                                         K.c.a.m.b.b.cS.a                          K.c.a.m.b.b.cS.aA                                                                         K.c.a.m.b.b.cT.a                                                                          K.c.a.m.b.b.cT.aA                                                                         K.c.a.m.b.b.kr.a                          K.c.a.m.b.b.kr.aA                                                                         K.c.a.ak.b.b.a.a                                                                          K.c.a.ak.b.b.a.aA                                                                         K.c.a.ak.b.b.m.a                          K.c.a.ak.b.b.m.aA                                                                         K.c.a.ak.b.b.ak.a                                                                         K.c.a.ak.b.b.ak.aA                                                                        K.c.a.ak.b.b.cP.a                         K.c.a.ak.b.b.cP.aA                                                                        K.c.a.ak.b.b.cS.a                                                                         K.c.a.ak.b.b.cS.aA                                                                        K.c.a.ak.b.b.cT.a                         K.c.a.ak.b.b.cT.aA                                                                        K.c.a.ak.b.b.kr.a                                                                         K.c.a.ak.b.b.kr.aA                                                                        K.c.a.cP.b.b.a.a                          K.c.a.cP.b.b.a.aA                                                                         K.c.a.cP.b.b.m.a                                                                          K.c.a.cP.b.b.m.aA                                                                         K.c.a.cP.b.b.ak.a                         K.c.a.cP.b.b.ak.aA                                                                        K.c.a.cP.b.b.cP.a                                                                         K.c.a.cP.b.b.cP.aA                                                                        K.c.a.cP.b.b.cS.a                         K.c.a.cP.b.b.cS.aA                                                                        K.c.a.cP.b.b.cT.a                                                                         K.c.a.cP.b.b.cT.aA                                                                        K.c.a.cP.b.b.kr.a                         K.c.a.cP.b.b.kr.aA                                                                        K.c.a.cS.b.b.a.a                                                                          K.c.a.cS.b.b.a.aA                                                                         K.c.a.cS.b.b.m.a                          K.c.a.cS.b.b.m.aA                                                                         K.c.a.cS.b.b.ak.a                                                                         K.c.a.cS.b.b.ak.aA                                                                        K.c.a.cS.b.b.cP.a                         K.c.a.cS.b.b.cP.aA                                                                        K.c.a.cS.b.b.cS.a                                                                         K.c.a.cS.b.b.cS.aA                                                                        K.c.a.cS.b.b.cT.a                         K.c.a.cS.b.b.cT.aA                                                                        K.c.a.cS.b.b.kr.a                                                                         K.c.a.cS.b.b.kr.aA                                                                        K.c.a.cT.b.b.a.a                          K.c.a.cT.b.b.a.aA                                                                         K.c.a.cT.b.b.m.a                                                                          K.c.a.cT.b.b.m.aA                                                                         K.c.a.cT.b.b.ak.a                         K.c.a.cT.b.b.ak.aA                                                                        K.c.a.cT.b.b.cP.a                                                                         K.c.a.cT.b.b.cP.aA                                                                        K.c.a.cT.b.b.cS.a                         K.c.a.cT.b.b.cS.aA                                                                        K.c.a.cT.b.b.cT.a                                                                         K.c.a.cT.b.b.cT.aA                                                                        K.c.a.cT.b.b.kr.a                         K.c.a.cT.b.b.kr.aA                                                                        K.c.a.kr.b.b.a.a                                                                          K.c.a.kr.b.b.a.aA                                                                         K.c.a.kr.b.b.m.a                          K.c.a.kr.b.b.m.aA                                                                         K.c.a.kr.b.b.ak.a                                                                         K.c.a.kr.b.b.ak.aA                                                                        K.c.a.kr.b.b.cP.a                         K.c.a.kr.b.b.cP.aA                                                                        K.c.a.kr.b.b.cS.a                                                                         K.c.a.kr.b.b.cS.aA                                                                        K.c.a.kr.b.b.cT.a                         K.c.a.kr.b.b.cT.aA                                                                        K.c.a.kr.b.b.kr.a                                                                         K.c.a.kr.b.b.kr.aA                                                                        K.c.aA.a.b.b.a.a                          K.c.aA.a.b.b.a.aA                                                                         K.c.aA.a.b.b.m.a                                                                          K.c.aA.a.b.b.m.aA                                     K.c.aA.a.b.b.ak.a                                                                         K.c.aA.a.b.b.ak.aA                                                                        K.c.aA.a.b.b.cP.a                                     K.c.aA.a.b.b.cP.aA                                                                        K.c.aA.a.b.b.cS.a                                                                         K.c.aA.a.b.b.cS.aA                                    K.c.aA.a.b.b.cT.a                                                                         K.c.aA.a.b.b.cT.aA                                                                        K.c.aA.a.b.b.kr.a                                     K.c.aA.a.b.b.kr.aA                                                                        K.c.aA.m.b.b.a.a                                                                          K.c.aA.m.b.b.a.aA                                     K.c.aA.m.b.b.m.a                                                                          K.c.aA.m.b.b.m.aA                                                                         K.c.aA.m.b.b.ak.a                                     K.c.aA.m.b.b.ak.aA                                                                        K.c.aA.m.b.b.cP.a                                                                         K.c.aA.m.b.b.cP.aA                                    K.c.aA.m.b.b.cS.a                                                                         K.c.aA.m.b.b.cS.aA                                                                        K.c.aA.m.b.b.cT.a                                     K.c.aA.m.b.b.cT.aA                                                                        K.c.aA.m.b.b.kr.a                                                                         K.c.aA.m.b.b.kr.aA                                    K.c.aA.ak.b.b.a.a                                                                         K.c.aA.ak.b.b.a.aA                                                                        K.c.aA.ak.b.b.m.a                                     K.c.aA.ak.b.b.m.aA                                                                        K.c.aA.ak.b.b.ak.a                                                                        K.c.aA.ak.b.b.ak.aA                                   K.c.aA.ak.b.b.cP.a                                                                        K.c.aA.ak.b.b.cP.aA                                                                       K.c.aA.ak.b.b.cS.a                                    K.c.aA.ak.b.b.cS.aA                                                                       K.c.aA.ak.b.b.cT.a                                                                        K.c.aA.ak.b.b.cT.aA                                   K.c.aA.ak.b.b.kr.a                                                                        K.c.aA.ak.b.b.kr.aA                                                                       K.c.aA.cP.b.b.a.a                                     K.c.aA.cP.b.b.a.aA                                                                        K.c.aA.cP.b.b.m.a                                                                         K.c.aA.cP.b.b.m.aA                                    K.c.aA.cP.b.b.ak.a                                                                        K.c.aA.cP.b.b.ak.aA                                                                       K.c.aA.cP.b.b.cP.a                                    K.c.aA.cP.b.b.cP.aA                                                                       K.c.aA.cP.b.b.cS.a                                                                        K.c.aA.cP.b.b.cS.aA                                   K.c.aA.cP.b.b.cT.a                                                                        K.c.aA.cP.b.b.cT.aA                                                                       K.c.aA.cP.b.b.kr.a                                    K.c.aA.cP.b.b.kr.aA                                                                       K.c.aA.cS.b.b.a.a                                                                         K.c.aA.cS.b.b.a.aA                                    K.c.aA.cS.b.b.m.a                                                                         K.c.aA.cS.b.b.m.aA                                                                        K.c.aA.cS.b.b.ak.a                                    K.c.aA.cS.b.b.ak.aA                                                                       K.c.aA.cS.b.b.cP.a                                                                        K.c.aA.cS.b.b.cP.aA                                   K.c.aA.cS.b.b.cS.a                                                                        K.c.aA.cS.b.b.cS.aA                                                                       K.c.aA.cS.b.b.cT.a                                    K.c.aA.cS.b.b.cT.aA                                                                       K.c.aA.cS.b.b.kr.a                                                                        K.c.aA.cS.b.b.kr.aA                                   K.c.aA.cT.b.b.a.a                                                                         K.c.aA.cT.b.b.a.aA                                                                        K.c.aA.cT.b.b.m.a                                     K.c.aA.cT.b.b.m.aA                                                                        K.c.aA.cT.b.b.ak.a                                                                        K.c.aA.cT.b.b.ak.aA                                   K.c.aA.cT.b.b.cP.a                                                                        K.c.aA.cT.b.b.cP.aA                                                                       K.c.aA.cT.b.b.cS.a                                    K.c.aA.cT.b.b.cS.aA                                                                       K.c.aA.cT.b.b.cT.a                                                                        K.c.aA.cT.b.b.cT.aA                                   K.c.aA.cT.b.b.kr.a                                                                        K.c.aA.cT.b.b.kr.aA                                                                       K.c.aA.kr.b.b.a.a                                     K.c.aA.kr.b.b.a.aA                                                                        K.c.aA.kr.b.b.m.a                                                                         K.c.aA.kr.b.b.m.aA                                    K.c.aA.kr.b.b.ak.a                                                                        K.c.aA.kr.b.b.ak.aA                                                                       K.c.aA.kr.b.b.cP.a                                    K.c.aA.kr.b.b.cP.aA                                                                       K.c.aA.kr.b.b.cS.a                                                                        K.c.aA.kr.b.b.cS.aA                                   K.c.aA.kr.b.b.cT.a                                                                        K.c.aA.kr.b.b.cT.aA                                                                       K.c.aA.kr.b.b.kr.a                                    K.c.aA.kr.b.b.kr.aA                                                                       L.c.a.a.b.b.a.a                                                                           L.c.a.a.b.b.a.aA                                                                          L.c.a.a.b.b.m.a                           L.c.a.a.b.b.m.aA                                                                          L.c.a.a.b.b.ak.a                                                                          L.c.a.a.b.b.ak.aA                                                                         L.c.a.a.b.b.cP.a                          L.c.a.a.b.b.cP.aA                                                                         L.c.a.a.b.b.cS.a                                                                          L.c.a.a.b.b.cS.aA                                                                         L.c.a.a.b.b.cT.a                          L.c.a.a.b.b.cT.aA                                                                         L.c.a.a.b.b.kr.a                                                                          L.c.a.a.b.b.kr.aA                                                                         L.c.a.m.b.b.a.a                           L.c.a.m.b.b.a.aA                                                                          L.c.a.m.b.b.m.a                                                                           L.c.a.m.b.b.m.aA                                                                          L.c.a.m.b.b.ak.a                          L.c.a.m.b.b.ak.aA                                                                         L.c.a.m.b.b.cP.a                                                                          L.c.a.m.b.b.cP.aA                                                                         L.c.a.m.b.b.cS.a                          L.c.a.m.b.b.cS.aA                                                                         L.c.a.m.b.b.cT.a                                                                          L.c.a.m.b.b.cT.aA                                                                         L.c.a.m.b.b.kr.a                          L.c.a.m.b.b.kr.aA                                                                         L.c.a.ak.b.b.a.a                                                                          L.c.a.ak.b.b.a.aA                                                                         L.c.a.ak.b.b.m.a                          L.c.a.ak.b.b.m.aA                                                                         L.c.a.ak.b.b.ak.a                                                                         L.c.a.ak.b.b.ak.aA                                                                        L.c.a.ak.b.b.cP.a                         L.c.a.ak.b.b.cP.aA                                                                        L.c.a.ak.b.b.cS.a                                                                         L.c.a.ak.b.b.cS.aA                                                                        L.c.a.ak.b.b.cT.a                         L.c.a.ak.b.b.cT.aA                                                                        L.c.a.ak.b.b.kr.a                                                                         L.c.a.ak.b.b.kr.aA                                                                        L.c.a.cP.b.b.a.a                          L.c.a.cP.b.b.a.aA                                                                         L.c.a.cP.b.b.m.a                                                                          L.c.a.cP.b.b.m.aA                                                                         L.c.a.cP.b.b.ak.a                         L.c.a.cP.b.b.ak.aA                                                                        L.c.a.cP.b.b.cP.a                                                                         L.c.a.cP.b.b.cP.aA                                                                        L.c.a.cP.b.b.cS.a                         L.c.a.cP.b.b.cS.aA                                                                        L.c.a.cP.b.b.cT.a                                                                         L.c.a.cP.b.b.cT.aA                                                                        L.c.a.cP.b.b.kr.a                         L.c.a.cP.b.b.kr.aA                                                                        L.c.a.cS.b.b.a.a                                                                          L.c.a.cS.b.b.a.aA                                                                         L.c.a.cS.b.b.m.a                          L.c.a.cS.b.b.m.aA                                                                         L.c.a.cS.b.b.ak.a                                                                         L.c.a.cS.b.b.ak.aA                                                                        L.c.a.cS.b.b.cP.a                         L.c.a.cS.b.b.cP.aA                                                                        L.c.a.cS.b.b.cS.a                                                                         L.c.a.cS.b.b.cS.aA                                                                        L.c.a.cS.b.b.cT.a                         L.c.a.cS.b.b.cT.aA                                                                        L.c.a.cS.b.b.kr.a                                                                         L.c.a.cS.b.b.kr.aA                                                                        L.c.a.cT.b.b.a.a                          L.c.a.cT.b.b.a.aA                                                                         L.c.a.cT.b.b.m.a                                                                          L.c.a.cT.b.b.m.aA                                                                         L.c.a.cT.b.b.ak.a                         L.c.a.cT.b.b.ak.aA                                                                        L.c.a.cT.b.b.cP.a                                                                         L.c.a.cT.b.b.cP.aA                                                                        L.c.a.cT.b.b.cS.a                         L.c.a.cT.b.b.cS.aA                                                                        L.c.a.cT.b.b.cT.a                                                                         L.c.a.cT.b.b.cT.aA                                                                        L.c.a.cT.b.b.kr.a                         L.c.a.cT.b.b.kr.aA                                                                        L.c.a.kr.b.b.a.a                                                                          L.c.a.kr.b.b.a.aA                                                                         L.c.a.kr.b.b.m.a                          L.c.a.kr.b.b.m.aA                                                                         L.c.a.kr.b.b.ak.a                                                                         L.c.a.kr.b.b.ak.aA                                                                        L.c.a.kr.b.b.cP.a                         L.c.a.kr.b.b.cP.aA                                                                        L.c.a.kr.b.b.cS.a                                                                         L.c.a.kr.b.b.cS.aA                                                                        L.c.a.kr.b.b.cT.a                         L.c.a.kr.b.b.cT.aA                                                                        L.c.a.kr.b.b.kr.a                                                                         L.c.a.kr.b.b.kr.aA                                                                        L.c.aA.a.b.b.a.a                          L.c.aA.a.b.b.a.aA                                                                         L.c.aA.a.b.b.m.a                                                                          L.c.aA.a.b.b.m.aA                                                                         L.c.aA.a.b.b.ak.a                         L.c.aA.a.b.b.ak.aA                                                                        L.c.aA.a.b.b.cP.a                                                                         L.c.aA.a.b.b.cP.aA                                                                        L.c.aA.a.b.b.cS.a                         L.c.aA.a.b.b.cS.aA                                                                        L.c.aA.a.b.b.cT.a                                                                         L.c.aA.a.b.b.cT.aA                                                                        L.c.aA.a.b.b.kr.a                         L.c.aA.a.b.b.kr.aA                                                                        L.c.aA.m.b.b.a.a                                                                          L.c.aA.m.b.b.a.aA                                                                         L.c.aA.m.b.b.m.a                          L.c.aA.m.b.b.m.aA                                                                         L.c.aA.m.b.b.ak.a                                                                         L.c.aA.m.b.b.ak.aA                                    L.c.aA.m.b.b.cP.a                                                                         L.c.aA.m.b.b.cP.aA                                                                        L.c.aA.m.b.b.cS.a                                     L.c.aA.m.b.b.cS.aA                                                                        L.c.aA.m.b.b.cT.a                                                                         L.c.aA.m.b.b.cT.aA                                    L.c.aA.m.b.b.kr.a                                                                         L.c.aA.m.b.b.kr.aA                                                                        L.c.aA.ak.b.b.a.a                                     L.c.aA.ak.b.b.a.aA                                                                        L.c.aA.ak.b.b.m.a                                                                         L.c.aA.ak.b.b.m.aA                                    L.c.aA.ak.b.b.ak.a                                                                        L.c.aA.ak.b.b.ak.aA                                                                       L.c.aA.ak.b.b.cP.a                                    L.c.aA.ak.b.b.cP.aA                                                                       L.c.aA.ak.b.b.cS.a                                                                        L.c.aA.ak.b.b.cS.aA                                   L.c.aA.ak.b.b.cT.a                                                                        L.c.aA.ak.b.b.cT.aA                                                                       L.c.aA.ak.b.b.kr.a                                    L.c.aA.ak.b.b.kr.aA                                                                       L.c.aA.cP.b.b.a.a                                                                         L.c.aA.cP.b.b.a.aA                                                                        L.c.aA.cP.b.b.m.a                         L.c.aA.cP.b.b.m.aA                                                                        L.c.aA.cP.b.b.ak.a                                                                        L.c.aA.cP.b.b.ak.aA                                   L.c.aA.cP.b.b.cP.a                                                                        L.c.aA.cP.b.b.cP.aA                                                                       L.c.aA.cP.b.b.cS.a                                    L.c.aA.cP.b.b.cS.aA                                                                       L.c.aA.cP.b.b.cT.a                                                                        L.c.aA.cP.b.b.cT.aA                                   L.c.aA.cP.b.b.kr.a                                                                        L.c.aA.cP.b.b.kr.aA                                                                       L.c.aA.cS.b.b.a.a                                                                         L.c.aA.cS.b.b.a.aA                        L.c.aA.cS.b.b.m.a                                                                         L.c.aA.cS.b.b.m.aA                                                                        L.c.aA.cS.b.b.ak.a                                    L.c.aA.cS.b.b.ak.aA                                                                       L.c.aA.cS.b.b.cP.a                                                                        L.c.aA.cS.b.b.cP.aA                                   L.c.aA.cS.b.b.cS.a                                                                        L.c.aA.cS.b.b.cS.aA                                                                       L.c.aA.cS.b.b.cT.a                                    L.c.aA.cS.b.b.cT.aA                                                                       L.c.aA.cS.b.b.kr.a                                                                        L.c.aA.cS.b.b.kr.aA                                                                       L.c.aA.cT.b.b.a.a                         L.c.aA.cT.b.b.a.aA                                                                        L.c.aA.cT.b.b.m.a                                                                         L.c.aA.cT.b.b.m.aA                                    L.c.aA.cT.b.b.ak.a                                                                        L.c.aA.cT.b.b.ak.aA                                                                       L.c.aA.cT.b.b.cP.a                                    L.c.aA.cT.b.b.cP.aA                                                                       L.c.aA.cT.b.b.cS.a                                                                        L.c.aA.cT.b.b.cS.aA                                   L.c.aA.cT.b.b.cT.a                                                                        L.c.aA.cT.b.b.cT.aA                                                                       L.c.aA.cT.b.b.kr.a                                    L.c.aA.cT.b.b.kr.aA                                                                       L.c.aA.kr.b.b.a.a                                                                         L.c.aA.kr.b.b.a.aA                                                                        L.c.aA.kr.b.b.m.a                         L.c.aA.kr.b.b.m.aA                                                                        L.c.aA.kr.b.b.ak.a                                                                        L.c.aA.kr.b.b.ak.aA                                   L.c.aA.kr.b.b.cP.a                                                                        L.c.aA.kr.b.b.cP.aA                                                                       L.c.aA.kr.b.b.cS.a                                    L.c.aA.kr.b.b.cS.aA                                                                       L.c.aA.kr.b.b.cT.a                                                                        L.c.aA.kr.b.b.cT.aA                                   L.c.aA.kr.b.b.kr.a                                                                        L.c.aA.kr.b.b.kr.aA                                                                       M.c.a.a.b.b.a.a                                                                           M.c.a.a.b.b.a.aA                          M.c.a.a.b.b.m.a                                                                           M.c.a.a.b.b.m.aA                                                                          M.c.a.a.b.b.ak.a                                                                          M.c.a.a.b.b.ak.aA                         M.c.a.a.b.b.cP.a                                                                          M.c.a.a.b.b.cP.aA                                                                         M.c.a.a.b.b.cS.a                                                                          M.c.a.a.b.b.cS.aA                         M.c.a.a.b.b.cT.a                                                                          M.c.a.a.b.b.cT.aA                                                                         M.c.a.a.b.b.kr.a                                                                          M.c.a.a.b.b.kr.aA                         M.c.a.m.b.b.a.a                                                                           M.c.a.m.b.b.a.aA                                                                          M.c.a.m.b.b.m.a                                                                           M.c.a.m.b.b.m.aA                          M.c.a.m.b.b.ak.a                                                                          M.c.a.m.b.b.ak.aA                                                                         M.c.a.m.b.b.cP.a                                      M.c.a.m.b.b.cP.aA                                                                         M.c.a.m.b.b.cS.a                                                                          M.c.a.m.b.b.cS.aA                                                                         M.c.a.m.b.b.cT.a                          M.c.a.m.b.b.cT.aA                                                                         M.c.a.m.b.b.kr.a                                                                          M.c.a.m.b.b.kr.aA                                                                         M.c.a.ak.b.b.a.a                          M.c.a.ak.b.b.a.aA                                                                         M.c.a.ak.b.b.m.a                                                                          M.c.a.ak.b.b.m.aA                                     M.c.a.ak.b.b.ak.a                                                                         M.c.a.ak.b.b.ak.aA                                                                        M.c.a.ak.b.b.cP.a                                     M.c.a.ak.b.b.cP.aA                                                                        M.c.a.ak.b.b.cS.a                                                                         M.c.a.ak.b.b.cS.aA                                    M.c.a.ak.b.b.cT.a                                                                         M.c.a.ak.b.b.cT.aA                                                                        M.c.a.ak.b.b.kr.a                                     M.c.a.ak.b.b.kr.aA                                                                        M.c.a.cP.b.b.a.a                                                                          M.c.a.cP.b.b.a.aA                                                                         M.c.a.cP.b.b.m.a                          M.c.a.cP.b.b.m.aA                                                                         M.c.a.cP.b.b.ak.a                                                                         M.c.a.cP.b.b.ak.aA                                                                        M.c.a.cP.b.b.cP.a                         M.c.a.cP.b.b.cP.aA                                                                        M.c.a.cP.b.b.cS.a                                                                         M.c.a.cP.b.b.cS.aA                                                                        M.c.a.cP.b.b.cT.a                         M.c.a.cP.b.b.cT.aA                                                                        M.c.a.cP.b.b.kr.a                                                                         M.c.a.cP.b.b.kr.aA                                                                        M.c.a.cS.b.b.a.a                          M.c.a.cS.b.b.a.aA                                                                         M.c.a.cS.b.b.m.a                                                                          M.c.a.cS.b.b.m.aA                                                                         M.c.a.cS.b.b.ak.a                         M.c.a.cS.b.b.ak.aA                                                                        M.c.a.cS.b.b.cP.a                                                                         M.c.a.cS.b.b.cP.aA                                                                        M.c.a.cS.b.b.cS.a                         M.c.a.cS.b.b.cS.aA                                                                        M.c.a.cS.b.b.cT.a                                                                         M.c.a.cS.b.b.cT.aA                                                                        M.c.a.cS.b.b.kr.a                         M.c.a.cS.b.b.kr.aA                                                                        M.c.a.cT.b.b.a.a                                                                          M.c.a.cT.b.b.a.aA                                                                         M.c.a.cT.b.b.m.a                          M.c.a.cT.b.b.m.aA                                                                         M.c.a.cT.b.b.ak.a                                                                         M.c.a.cT.b.b.ak.aA                                                                        M.c.a.cT.b.b.cP.a                         M.c.a.cT.b.b.cP.aA                                                                        M.c.a.cT.b.b.cS.a                                                                         M.c.a.cT.b.b.cS.aA                                    M.c.a.cT.b.b.cT.a                                                                         M.c.a.cT.b.b.cT.aA                                                                        M.c.a.cT.b.b.kr.a                                     M.c.a.cT.b.b.kr.aA                                                                        M.c.a.kr.b.b.a.a                                                                          M.c.a.kr.b.b.a.aA                                                                         M.c.a.kr.b.b.m.a                          M.c.a.kr.b.b.m.aA                                                                         M.c.a.kr.b.b.ak.a                                                                         M.c.a.kr.b.b.ak.aA                                                                        M.c.a.kr.b.b.cP.a                         M.c.a.kr.b.b.cP.aA                                                                        M.c.a.kr.b.b.cS.a                                                                         M.c.a.kr.b.b.cS.aA                                                                        M.c.a.kr.b.b.cT.a                         M.c.a.kr.b.b.cT.aA                                                                        M.c.a.kr.b.b.kr.a                                                                         M.c.a.kr.b.b.kr.aA                                                                        M.c.aA.a.b.b.a.a                          M.c.aA.a.b.b.a.aA                                                                         M.c.aA.a.b.b.m.a                                                                          M.c.aA.a.b.b.m.aA                                     M.c.aA.a.b.b.ak.a                                                                         M.c.aA.a.b.b.ak.aA                                                                        M.c.aA.a.b.b.cP.a                                     M.c.aA.a.b.b.cP.aA                                                                        M.c.aA.a.b.b.cS.a                                                                         M.c.aA.a.b.b.cS.aA                                    M.c.aA.a.b.b.cT.a                                                                         M.c.aA.a.b.b.cT.aA                                                                        M.c.aA.a.b.b.kr.a                                     M.c.aA.a.b.b.kr.aA                                                                        M.c.aA.m.b.b.a.a                                                                          M.c.aA.m.b.b.a.aA                                     M.c.aA.m.b.b.m.a                                                                          M.c.aA.m.b.b.m.aA                                                                         M.c.aA.m.b.b.ak.a                                     M.c.aA.m.b.b.ak.aA                                                                        M.c.aA.m.b.b.cP.a                                                                         M.c.aA.m.b.b.cP.aA                                    M.c.aA.m.b.b.cS.a                                                                         M.c.aA.m.b.b.cS.aA                                                                        M.c.aA.m.b.b.cT.a                                     M.c.aA.m.b.b.cT.aA                                                                        M.c.aA.m.b.b.kr.a                                                                         M.c.aA.m.b.b.kr.aA                                    M.c.aA.ak.b.b.a.a                                                                         M.c.aA.ak.b.b.a.aA                                                                        M.c.aA.ak.b.b.m.a                                     M.c.aA.ak.b.b.m.aA                                                                        M.c.aA.ak.b.b.ak.a                                                                        M.c.aA.ak.b.b.ak.aA                                   M.c.aA.ak.b.b.cP.a                                                                        M.c.aA.ak.b.b.cP.aA                                                                       M.c.aA.ak.b.b.cS.a                                    M.c.aA.ak.b.b.cS.aA                                                                       M.c.aA.ak.b.b.cT.a                                                                        M.c.aA.ak.b.b.cT.aA                                   M.c.aA.ak.b.b.kr.a                                                                        M.c.aA.ak.b.b.kr.aA                                                                       M.c.aA.cP.b.b.a.a                                     M.c.aA.cP.b.b.a.aA                                                                        M.c.aA.cP.b.b.m.a                                                                         M.c.aA.cP.b.b.m.aA                                    M.c.aA.cP.b.b.ak.a                                                                        M.c.aA.cP.b.b.ak.aA                                                                       M.c.aA.cP.b.b.cP.a                                    M.c.aA.cP.b.b.cP.aA                                                                       M.c.aA.cP.b.b.cS.a                                                                        M.c.aA.cP.b.b.cS.aA                                   M.c.aA.cP.b.b.cT.a                                                                        M.c.aA.cP.b.b.cT.aA                                                                       M.c.aA.cP.b.b.kr.a                                    M.c.aA.cP.b.b.kr.aA                                                                       M.c.aA.cS.b.b.a.a                                                                         M.c.aA.cS.b.b.a.aA                                    M.c.aA.cS.b.b.m.a                                                                         M.c.aA.cS.b.b.m.aA                                                                        M.c.aA.cS.b.b.ak.a                                    M.c.aA.cS.b.b.ak.aA                                                                       M.c.aA.cS.b.b.cP.a                                                                        M.c.aA.cS.b.b.cP.aA                                   M.c.aA.cS.b.b.cS.a                                                                        M.c.aA.cS.b.b.cS.aA                                                                       M.c.aA.cS.b.b.cT.a                                    M.c.aA.cS.b.b.cT.aA                                                                       M.c.aA.cS.b.b.kr.a                                                                        M.c.aA.cS.b.b.kr.aA                                   M.c.aA.cT.b.b.a.a                                                                         M.c.aA.cT.b.b.a.aA                                                                        M.c.aA.cT.b.b.m.a                                     M.c.aA.cT.b.b.m.aA                                                                        M.c.aA.cT.b.b.ak.a                                                                        M.c.aA.cT.b.b.ak.aA                                   M.c.aA.cT.b.b.cP.a                                                                        M.c.aA.cT.b.b.cP.aA                                                                       M.c.aA.cT.b.b.cS.a                                    M.c.aA.cT.b.b.cS.aA                                                                       M.c.aA.cT.b.b.cT.a                                                                        M.c.aA.cT.b.b.cT.aA                                   M.c.aA.cT.b.b.kr.a                                                                        M.c.aA.cT.b.b.kr.aA                                                                       M.c.aA.kr.b.b.a.a                                     M.c.aA.kr.b.b.a.aA                                                                        M.c.aA.kr.b.b.m.a                                                                         M.c.aA.kr.b.b.m.aA                                    M.c.aA.kr.b.b.ak.a                                                                        M.c.aA.kr.b.b.ak.aA                                                                       M.c.aA.kr.b.b.cP.a                                    M.c.aA.kr.b.b.cP.aA                                                                       M.c.aA.kr.b.b.cS.a                                                                        M.c.aA.kr.b.b.cS.aA                                   M.c.aA.kr.b.b.cT.a                                                                        M.c.aA.kr.b.b.cT.aA                                                                       M.c.aA.kr.b.b.kr.a                                    M.c.aA.kr.b.b.kr.aA                                                                       N.c.a.a.b.b.a.a                                                                           N.c.a.a.b.b.a.aA                                                                          N.c.a.a.b.b.m.a                           N.c.a.a.b.b.m.aA                                                                          N.c.a.a.b.b.ak.a                                                                          N.c.a.a.b.b.ak.aA                                                                         N.c.a.a.b.b.cP.a                          N.c.a.a.b.b.cP.aA                                                                         N.c.a.a.b.b.cS.a                                                                          N.c.a.a.b.b.cS.aA                                                                         N.c.a.a.b.b.cT.a                          N.c.a.a.b.b.cT.aA                                                                         N.c.a.a.b.b.kr.a                                                                          N.c.a.a.b.b.kr.aA                                                                         N.c.a.m.b.b.a.a                           N.c.a.m.b.b.a.aA                                                                          N.c.a.m.b.b.m.a                                                                           N.c.a.m.b.b.m.aA                                                                          N.c.a.m.b.b.ak.a                          N.c.a.m.b.b.ak.aA                                                                         N.c.a.m.b.b.cP.a                                                                          N.c.a.m.b.b.cP.aA                                                                         N.c.a.m.b.b.cS.a                          N.c.a.m.b.b.cS.aA                                                                         N.c.a.m.b.b.cT.a                                                                          N.c.a.m.b.b.cT.aA                                                                         N.c.a.m.b.b.kr.a                          N.c.a.m.b.b.kr.aA                                                                         N.c.a.ak.b.b.a.a                                                                          N.c.a.ak.b.b.a.aA                                                                         N.c.a.ak.b.b.m.a                          N.c.a.ak.b.b.m.aA                                                                         N.c.a.ak.b.b.ak.a                                                                         N.c.a.ak.b.b.ak.aA                                                                        N.c.a.ak.b.b.cP.a                         N.c.a.ak.b.b.cP.aA                                                                        N.c.a.ak.b.b.cS.a                                                                         N.c.a.ak.b.b.cS.aA                                                                        N.c.a.ak.b.b.cT.a                         N.c.a.ak.b.b.cT.aA                                                                        N.c.a.ak.b.b.kr.a                                                                         N.c.a.ak.b.b.kr.aA                                                                        N.c.a.cP.b.b.a.a                          N.c.a.cP.b.b.a.aA                                                                         N.c.a.cP.b.b.m.a                                                                          N.c.a.cP.b.b.m.aA                                                                         N.c.a.cP.b.b.ak.a                         N.c.a.cP.b.b.ak.aA                                                                        N.c.a.cP.b.b.cP.a                                                                         N.c.a.cP.b.b.cP.aA                                                                        N.c.a.cP.b.b.cS.a                         N.c.a.cP.b.b.cS.aA                                                                        N.c.a.cP.b.b.cT.a                                                                         N.c.a.cP.b.b.cT.aA                                                                        N.c.a.cP.b.b.kr.a                         N.c.a.cP.b.b.kr.aA                                                                        N.c.a.cS.b.b.a.a                                                                          N.c.a.cS.b.b.a.aA                                                                         N.c.a.cS.b.b.m.a                          N.c.a.cS.b.b.m.aA                                                                         N.c.a.cS.b.b.ak.a                                                                         N.c.a.cS.b.b.ak.aA                                                                        N.c.a.cS.b.b.cP.a                         N.c.a.cS.b.b.cP.aA                                                                        N.c.a.cS.b.b.cS.a                                                                         N.c.a.cS.b.b.cS.aA                                                                        N.c.a.cS.b.b.cT.a                         N.c.a.cS.b.b.cT.aA                                                                        N.c.a.cS.b.b.kr.a                                                                         N.c.a.cS.b.b.kr.aA                                                                        N.c.a.cT.b.b.a.a                          N.c.a.cT.b.b.a.aA                                                                         N.c.a.cT.b.b.m.a                                                                          N.c.a.cT.b.b.m.aA                                                                         N.c.a.cT.b.b.ak.a                         N.c.a.cT.b.b.ak.aA                                                                        N.c.a.cT.b.b.cP.a                                                                         N.c.a.cT.b.b.cP.aA                                                                        N.c.a.cT.b.b.cS.a                         N.c.a.cT.b.b.cS.aA                                                                        N.c.a.cT.b.b.cT.a                                                                         N.c.a.cT.b.b.cT.aA                                                                        N.c.a.cT.b.b.kr.a                         N.c.a.cT.b.b.kr.aA                                                                        N.c.a.kr.b.b.a.a                                                                          N.c.a.kr.b.b.a.aA                                                                         N.c.a.kr.b.b.m.a                          N.c.a.kr.b.b.m.aA                                                                         N.c.a.kr.b.b.ak.a                                                                         N.c.a.kr.b.b.ak.aA                                                                        N.c.a.kr.b.b.cP.a                         N.c.a.kr.b.b.cP.aA                                                                        N.c.a.kr.b.b.cS.a                                                                         N.c.a.kr.b.b.cS.aA                                                                        N.c.a.kr.b.b.cT.a                         N.c.a.kr.b.b.cT.aA                                                                        N.c.a.kr.b.b.kr.a                                                                         N.c.a.kr.b.b.kr.aA                                                                        N.c.aA.a.b.b.a.a                          N.c.aA.a.b.b.a.aA                                                                         N.c.aA.a.b.b.m.a                                                                          N.c.aA.a.b.b.m.aA                                     N.c.aA.a.b.b.ak.a                                                                         N.c.aA.a.b.b.ak.aA                                                                        N.c.aA.a.b.b.cP.a                                     N.c.aA.a.b.b.cP.aA                                                                        N.c.aA.a.b.b.cS.a                                                                         N.c.aA.a.b.b.cS.aA                                    N.c.aA.a.b.b.cT.a                                                                         N.c.aA.a.b.b.cT.aA                                                                        N.c.aA.a.b.b.kr.a                                     N.c.aA.a.b.b.kr.aA                                                                        N.c.aA.m.b.b.a.a                                                                          N.c.aA.m.b.b.a.aA                                     N.c.aA.m.b.b.m.a                                                                          N.c.aA.m.b.b.m.aA                                                                         N.c.aA.m.b.b.ak.a                                     N.c.aA.m.b.b.ak.aA                                                                        N.c.aA.m.b.b.cP.a                                                                         N.c.aA.m.b.b.cP.aA                                    N.c.aA.m.b.b.cS.a                                                                         N.c.aA.m.b.b.cS.aA                                                                        N.c.aA.m.b.b.cT.a                                     N.c.aA.m.b.b.cT.aA                                                                        N.c.aA.m.b.b.kr.a                                                                         N.c.aA.m.b.b.kr.aA                                    N.c.aA.ak.b.b.a.a                                                                         N.c.aA.ak.b.b.a.aA                                                                        N.c.aA.ak.b.b.m.a                                     N.c.aA.ak.b.b.m.aA                                                                        N.c.aA.ak.b.b.ak.a                                                                        N.c.aA.ak.b.b.ak.aA                                   N.c.aA.ak.b.b.cP.a                                                                        N.c.aA.ak.b.b.cP.aA                                                                       N.c.aA.ak.b.b.cS.a                                    N.c.aA.ak.b.b.cS.aA                                                                       N.c.aA.ak.b.b.cT.a                                                                        N.c.aA.ak.b.b.cT.aA                                   N.c.aA.ak.b.b.kr.a                                                                        N.c.aA.ak.b.b.kr.aA                                                                       N.c.aA.cP.b.b.a.a                                     N.c.aA.cP.b.b.a.aA                                                                        N.c.aA.cP.b.b.m.a                                                                         N.c.aA.cP.b.b.m.aA                                    N.c.aA.cP.b.b.ak.a                                                                        N.c.aA.cP.b.b.ak.aA                                                                       N.c.aA.cP.b.b.cP.a                                    N.c.aA.cP.b.b.cP.aA                                                                       N.c.aA.cP.b.b.cS.a                                                                        N.c.aA.cP.b.b.cS.aA                                   N.c.aA.cP.b.b.cT.a                                                                        N.c.aA.cP.b.b.cT.aA                                                                       N.c.aA.cP.b.b.kr.a                                    N.c.aA.cP.b.b.kr.aA                                                                       N.c.aA.cS.b.b.a.a                                                                         N.c.aA.cS.b.b.a.aA                                    N.c.aA.cS.b.b.m.a                                                                         N.c.aA.cS.b.b.m.aA                                                                        N.c.aA.cS.b.b.ak.a                                    N.c.aA.cS.b.b.ak.aA                                                                       N.c.aA.cS.b.b.cP.a                                                                        N.c.aA.cS.b.b.cP.aA                                   N.c.aA.cS.b.b.cS.a                                                                        N.c.aA.cS.b.b.cS.aA                                                                       N.c.aA.cS.b.b.cT.a                                    N.c.aA.cS.b.b.cT.aA                                                                       N.c.aA.cS.b.b.kr.a                                                                        N.c.aA.cS.b.b.kr.aA                                   N.c.aA.cT.b.b.a.a                                                                         N.c.aA.cT.b.b.a.aA                                                                        N.c.aA.cT.b.b.m.a                                     N.c.aA.cT.b.b.m.aA                                                                        N.c.aA.cT.b.b.ak.a                                                                        N.c.aA.cT.b.b.ak.aA                                   N.c.aA.cT.b.b.cP.a                                                                        N.c.aA.cT.b.b.cP.aA                                                                       N.c.aA.cT.b.b.cS.a                                    N.c.aA.cT.b.b.cS.aA                                                                       N.c.aA.cT.b.b.cT.a                                                                        N.c.aA.cT.b.b.cT.aA                                   N.c.aA.cT.b.b.kr.a                                                                        N.c.aA.cT.b.b.kr.aA                                                                       N.c.aA.kr.b.b.a.a                                     N.c.aA.kr.b.b.a.aA                                                                        N.c.aA.kr.b.b.m.a                                                                         N.c.aA.kr.b.b.m.aA                                    N.c.aA.kr.b.b.ak.a                                                                        N.c.aA.kr.b.b.ak.aA                                                                       N.c.aA.kr.b.b.cP.a                                    N.c.aA.kr.b.b.cP.aA                                                                       N.c.aA.kr.b.b.cS.a                                                                        N.c.aA.kr.b.b.cS.aA                                   N.c.aA.kr.b.b.cT.a                                                                        N.c.aA.kr.b.b.cT.aA                                                                       N.c.aA.kr.b.b.kr.a                                    N.c.aA.kr.b.b.kr.aA                                                                       O.c.a.a.b.b.a.a                                                                           O.c.a.a.b.b.a.aA                                                                          O.c.a.a.b.b.m.a                           O.c.a.a.b.b.m.aA                                                                          O.c.a.a.b.b.ak.a                                                                          O.c.a.a.b.b.ak.aA                                                                         O.c.a.a.b.b.cP.a                          O.c.a.a.b.b.cP.aA                                                                         O.c.a.a.b.b.cS.a                                                                          O.c.a.a.b.b.cS.aA                                                                         O.c.a.a.b.b.cT.a                          O.c.a.a.b.b.cT.aA                                                                         O.c.a.a.b.b.kr.a                                                                          O.c.a.a.b.b.kr.aA                                                                         O.c.a.m.b.b.a.a                           O.c.a.m.b.b.a.aA                                                                          O.c.a.m.b.b.m.a                                                                           O.c.a.m.b.b.m.aA                                                                          O.c.a.m.b.b.ak.a                          O.c.a.m.b.b.ak.aA                                                                         O.c.a.m.b.b.cP.a                                                                          O.c.a.m.b.b.cP.aA                                                                         O.c.a.m.b.b.cS.a                          O.c.a.m.b.b.cS.aA                                                                         O.c.a.m.b.b.cT.a                                                                          O.c.a.m.b.b.cT.aA                                                                         O.c.a.m.b.b.kr.a                          O.c.a.m.b.b.kr.aA                                                                         O.c.a.ak.b.b.a.a                                                                          O.c.a.ak.b.b.a.aA                                                                         O.c.a.ak.b.b.m.a                          O.c.a.ak.b.b.m.aA                                                                         O.c.a.ak.b.b.ak.a                                                                         O.c.a.ak.b.b.ak.aA                                                                        O.c.a.ak.b.b.cP.a                         O.c.a.ak.b.b.cP.aA                                                                        O.c.a.ak.b.b.cS.a                                                                         O.c.a.ak.b.b.cS.aA                                                                        O.c.a.ak.b.b.cT.a                         O.c.a.ak.b.b.cT.aA                                                                        O.c.a.ak.b.b.kr.a                                                                         O.c.a.ak.b.b.kr.aA                                                                        O.c.a.cP.b.b.a.a                          O.c.a.cP.b.b.a.aA                                                                         O.c.a.cP.b.b.m.a                                                                          O.c.a.cP.b.b.m.aA                                                                         O.c.a.cP.b.b.ak.a                         O.c.a.cP.b.b.ak.aA                                                                        O.c.a.cP.b.b.cP.a                                                                         O.c.a.cP.b.b.cP.aA                                                                        O.c.a.cP.b.b.cS.a                         O.c.a.cP.b.b.cS.aA                                                                        O.c.a.cPb.b.cT.a                                                                          O.c.a.cP.b.b.cT.aA                                                                        O.c.a.cP.b.b.kr.a                         O.c.a.cP.b.b.kr.aA                                                                        O.c.a.cS.b.b.a.a                                                                          O.c.a.cS.b.b.a.aA                                                                         O.c.a.cS.b.b.m.a                          O.c.a.cS.b.b.m.aA                                                                         O.c.a.cS.b.b.ak.a                                                                         O.c.a.cS.b.b.ak.aA                                                                        O.c.a.cS.b.b.cP.a                         O.c.a.cS.b.b.cP.aA                                                                        O.c.a.cS.b.b.cS.a                                                                         O.c.a.cS.b.b.cS.aA                                                                        O.c.a.cS.b.b.cT.a                         O.c.a.cS.b.b.cT.aA                                                                        O.c.a.cS.b.b.kr.a                                                                         O.c.a.cS.b.b.kr.aA                                                                        O.c.a.cT.b.b.a.a                          O.c.a.cT.b.b.a.aA                                                                         O.c.a.cT.b.b.m.a                                                                          O.c.a.cT.b.b.m.aA                                                                         O.c.a.cT.b.b.ak.a                         O.c.a.cT.b.b.ak.aA                                                                        O.c.a.cT.b.b.cP.a                                                                         O.c.a.cT.b.b.cP.aA                                                                        O.c.a.cT.b.b.cS.a                         O.c.a.cT.b.b.cS.aA                                                                        O.c.a.cT.b.b.cT.a                                                                         O.c.a.cT.b.b.cT.aA                                                                        O.c.a.cT.b.b.kr.a                         O.c.a.cT.b.b.kr.aA                                                                        O.c.a.kr.b.b.a.a                                                                          O.c.a.kr.b.b.a.aA                                                                         O.c.a.kr.b.b.m.a                          O.c.a.kr.b.b.m.aA                                                                         O.c.a.kr.b.b.ak.a                                                                         O.c.a.kr.b.b.ak.aA                                                                        O.c.a.kr.b.b.cP.a                         O.c.a.kr.b.b.cP.aA                                                                        O.c.a.kr.b.b.cS.a                                                                         O.c.a.kr.bb.cS.aA                                                                         O.c.a.kr.b.b.cT.a                         O.c.a.kr.b.b.cT.aA                                                                        O.c.a.kr.b.b.kr.a                                                                         O.c.a.kr.b.b.kr.aA                                                                        O.c.aA.a.b.b.a.a                          O.c.aA.a.b.b.a.aA                                                                         O.c.aA.a.b.b.m.a                                                                          O.c.aA.a.b.b.m.aA                                     O.c.aA.a.b.b.ak.a                                                                         O.c.aA.a.b.b.ak.aA                                                                        O.c.aA.a.b.b.cP.a                                     O.c.aA.a.b.b.cP.aA                                                                        O.c.aA.a.b.b.cS.a                                                                         O.c.aA.a.b.b.cS.aA                                    O.c.aA.a.b.b.cT.a                                                                         O.c.aA.a.b.b.cT.aA                                                                        O.c.aA.a.b.b.kr.a                                     O.c.aA.a.b.b.kr.aA                                                                        O.c.aA.m.b.b.a.a                                                                          O.c.aA.m.b.b.a.aA                                     O.c.aA.m.b.b.m.a                                                                          O.c.aA.m.b.b.m.aA                                                                         O.c.aA.m.b.b.ak.a                                     O.c.aA.m.b.b.ak.aA                                                                        O.c.aA.m.b.b.cP.a                                                                         O.c.aA.m.b.b.cP.aA                                    O.c.aA.m.b.b.cS.a                                                                         O.c.aA.m.b.b.cS.aA                                                                        O.c.aA.m.b.b.cT.a                                     O.c.aA.m.b.b.cT.aA                                                                        O.c.aA.m.b.b.kr.a                                                                         O.c.aA.m.b.b.kr.aA                                    O.c.aA.ak.b.b.a.a                                                                         O.c.aA.ak.b.b.a.aA                                                                        O.c.aA.ak.b.b.m.a                                     O.c.aA.ak.b.b.m.aA                                                                        O.c.aA.ak.b.b.ak.a                                                                        O.c.aA.ak.b.b.ak.aA                                   O.c.aA.ak.b.b.cP.a                                                                        O.c.aA.ak.b.b.cP.aA                                                                       O.c.aA.ak.b.b.cS.a                                    O.c.aA.ak.b.b.cS.aA                                                                       O.c.aA.ak.b.b.cT.a                                                                        O.c.aA.ak.b.b.cT.aA                                   O.c.aA.ak.b.b.kr.a                                                                        O.c.aA.ak.b.b.kr.aA                                                                       O.c.aA.cP.b.b.a.a                                     O.c.aA.cP.b.b.a.aA                                                                        O.c.aA.cP.b.b.m.a                                                                         O.c.aA.cP.b.b.m.aA                                    O.c.aA.cP.b.b.ak.a                                                                        O.c.aA.cP.b.b.ak.aA                                                                       O.c.aA.cP.b.b.cP.a                                    O.c.aA.cP.b.b.cP.aA                                                                       O.c.aA.cP.b.b.cS.a                                                                        O.c.aA.cP.b.b.cS.aA                                   O.c.aA.cP.b.b.cT.a                                                                        O.c.aA.cP.b.b.cT.aA                                                                       O.c.aA.cP.b.b.kr.a                                    O.c.aA.cP.b.b.kr.aA                                                                       O.c.aA.cS.b.b.a.a                                                                         O.c.aA.cS.b.b.a.aA                                    O.c.aA.cS.b.b.m.a                                                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                                                  O.c.aA.cT.b.b.m.a                                     O.c.aA.cT.b.b.m.aA                                                                        O.c.aA.cT.b.b.ak.a                                                                        O.c.aA.cT.b.b.ak.aA                                   O.c.aA.cT.b.b.cP.a                                                                        O.c.aA.cT.b.b.cP.aA                                                                       O.c.aA.cT.b.b.cS.a                                    O.c.aA.cT.b.b.cS.aA                                                                       O.c.aA.cT.b.b.cT.a                                                                        O.c.aA.cT.b.b.cT.aA                                   O.c.aA.cT.b.b.kr.a                                                                        O.c.aA.cT.b.b.kr.aA                                                                       O.c.aA.kr.b.b.a.a                                     O.c.aA.kr.b.b.a.aA                                                                        O.c.aA.kr.b.b.m.a                                                                         O.c.aA.kr.b.b.m.aA                                    O.c.aA.kr.b.b.ak.a                                                                        O.c.aA.kr.b.b.ak.aA                                                                       O.c.aA.kr.b.b.cP.a                                    O.c.aA.kr.b.b.cP.aA                                                                       O.c.aA.kr.b.b.cS.a                                                                        O.c.aA.kr.b.b.cS.aA                                   O.c.aA.kr.b.b.cT.a                                                                        O.c.aA.kr.b.b.cT.aA                                                                       O.c.aA.kr.b.b.kr.a                                    O.c.aA.kr.b.b.kr.aA                                                                       P.c.a.a.b.b.a.a                                                                           P.c.a.a.b.b.a.aA                                                                          P.c.a.a.b.b.m.a                           P.c.a.a.b.b.m.aA                                                                          P.c.a.a.b.b.ak.a                                                                          P.c.a.a.b.b.ak.aA                                                                         P.c.a.a.b.b.cP.a                          P.c.a.a.b.b.cP.aA                                                                         P.c.a.a.b.b.cS.a                                                                          P.c.a.a.b.b.cS.aA                                                                         P.c.a.a.b.b.cT.a                          P.c.a.a.b.b.cT.aA                                                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P.c.a.ak.b.b.cS.aA                                                                        P.c.a.ak.b.b.cT.a                         P.c.a.ak.b.b.cT.aA                                                                        P.c.a.ak.b.b.kr.a                                                                         P.c.a.ak.b.b.kr.aA                                                                        P.c.a.cP.b.b.a.a                          P.c.a.cP.b.b.a.aA                                                                         P.c.a.cP.b.b.m.a                                                                          P.c.a.cP.b.b.m.aA                                                                         P.c.a.cP.b.b.ak.a                         P.c.a.cP.b.b.ak.aA                                                                        P.c.a.cP.b.b.cP.a                                                                         P.c.a.cP.b.b.cP.aA                                                                        P.c.a.cP.b.b.cS.a                         P.c.a.cP.b.b.cS.aA                                                                        P.c.a.cP.b.b.cT.a                                                                         P.c.a.cP.b.b.cT.aA                                                                        P.c.a.cP.b.b.kr.a                         P.c.a.cP.b.b.kr.aA                                                                        P.c.a.cS.b.b.a.a                                                                          P.c.a.cS.b.b.a.aA                                                                         P.c.a.cS.b.b.m.a                          P.c.a.cS.b.b.m.aA                                                                         P.c.a.cS.b.b.ak.a                                                                         P.c.a.cS.b.b.ak.aA                                                                        P.c.a.cS.b.b.cP.a                         P.c.a.cS.b.b.cP.aA                                                                        P.c.a.cS.b.b.cS.a                                                                         P.c.a.cS.b.b.cS.aA                                                                        P.c.a.cS.b.b.cT.a                         P.c.a.cS.b.b.cT.aA                                                                        P.c.a.cS.b.b.kr.a                                                                         P.c.a.cS.b.b.kr.aA                                                                        P.c.a.cT.b.b.a.a                          P.c.a.cT.b.b.a.aA                                                                         P.c.a.cT.b.b.m.a                                                                          P.c.a.cT.b.b.m.aA                                                                         P.c.a.cT.b.b.ak.a                         P.c.a.cT.b.b.ak.aA                                                                        P.c.a.cT.b.b.cP.a                                                                         P.c.a.cT.b.b.cP.aA                                                                        P.c.a.cT.b.b.cS.a                         P.c.a.cT.b.b.cS.aA                                                                        P.c.a.cT.b.b.cT.a                                                                         P.c.a.cT.b.b.cT.aA                                                                        P.c.a.cT.b.b.kr.a                         P.c.a.cT.b.b.kr.aA                                                                        P.c.a.kr.b.b.a.a                                                                          P.c.a.kr.b.b.a.aA                                                                         P.c.a.kr.b.b.m.a                          P.c.a.kr.b.b.m.aA                                                                         P.c.a.kr.b.b.ak.a                                                                         P.c.a.kr.b.b.ak.aA                                                                        P.c.a.kr.b.b.cP.a                         P.c.a.kr.b.b.cP.aA                                                                        P.c.a.kr.b.b.cS.a                                                                         P.c.a.kr.b.b.cS.aA                                                                        P.c.a.kr.b.b.cT.a                         P.c.a.kr.b.b.cT.aA                                                                        P.c.a.kr.b.b.kr.a                                                                         P.c.a.kr.b.b.kr.aA                                                                        P.c.aA.a.b.b.a.a                          P.c.aA.a.b.b.a.aA                                                                         P.c.aA.a.b.b.m.a                                                                          P.c.aA.a.b.b.m.aA                                                                         P.c.aA.a.b.b.ak.a                         P.c.aA.a.b.b.ak.aA                                                                        P.c.aA.a.b.b.cP.a                                                                         P.c.aA.a.b.b.cP.aA                                                                        P.c.aA.a.b.b.cS.a                         P.c.aA.a.b.b.cS.aA                                                                        P.c.aA.a.b.b.cT.a                                                                         P.c.aA.a.b.b.cT.aA                                                                        P.c.aA.a.b.b.kr.a                         P.c.aA.a.b.b.kr.aA                                                                        P.c.aA.m.b.b.a.a                                                                          P.c.aA.m.b.b.a.aA                                                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  P.c.aA.ak.b.b.a.aA                                                                        P.c.aA.ak.b.b.m.a                                                                         P.c.aA.ak.b.b.m.aA                                    P.c.aA.ak.b.b.ak.a                                                                        P.c.aA.ak.b.b.ak.aA                                                                       P.c.aA.ak.b.b.cP.a                                    P.c.aA.ak.b.b.cP.aA                                                                       P.c.aA.ak.b.b.cS.a                                                                        P.c.aA.ak.b.b.cS.aA                                   P.c.aA.ak.b.b.cT.a                                                                        P.c.aA.ak.b.b.cT.aA                                                                       P.c.aA.ak.b.b.kr.a                                    P.c.aA.ak.b.b.kr.aA                                                                       P.c.aA.cP.b.b.a.a                                                                         P.c.aA.cP.b.b.a.aA                                                                        P.c.aA.cP.b.b.m.a                         P.c.aA.cP.b.b.m.aA                                                                        P.c.aA.cP.b.b.ak.a                                                                        P.c.aA.cP.b.b.ak.aA                                   P.c.aA.cP.b.b.cP.a                                                                        P.c.aA.cP.b.b.cP.aA                                                                       P.c.aA.cP.b.b.cS.a                                    P.c.aA.cP.b.b.cS.aA                                                                       P.c.aA.cP.b.b.cT.a                                                                        P.c.aA.cP.b.b.cT.aA                                   P.c.aA.cP.b.b.kr.a                                                                        P.c.aA.cP.b.b.kr.aA                                                                       P.c.aA.cS.b.b.a.a                                                                         P.c.aA.cS.b.b.a.aA                        P.c.aA.cS.b.b.m.a                                                                         P.c.aA.cS.b.b.m.aA                                                                        P.c.aA.cS.b.b.ak.a                                    P.c.aA.cS.b.b.ak.aA                                                                       P.c.aA.cS.b.b.cP.a                                                                        P.c.aA.cS.b.b.cP.aA                                   P.c.aA.cS.b.b.cS.a                                                                        P.c.aA.cS.b.b.cS.aA                                                                       P.c.aA.cS.b.b.cT.a                                    P.c.aA.cS.b.b.cT.aA                                                                       P.c.aA.cS.b.b.kr.a                                                                        P.c.aA.cS.b.b.kr.aA                                                                       P.c.aA.cT.b.b.a.a                         P.c.aA.cT.b.b.a.aA                                                                        P.c.aA.cT.b.b.m.a                                                                         P.c.aA.cT.b.b.m.aA                                    P.c.aA.cT.b.b.ak.a                                                                        P.c.aA.cT.b.b.ak.aA                                                                       P.c.aA.cT.b.b.cP.a                                    P.c.aA.cT.b.b.cP.aA                                                                       P.c.aA.cT.b.b.cS.a                                                                        P.c.aA.cT.b.b.cS.aA                                   P.c.aA.cT.b.b.cT.a                                                                        P.c.aA.cT.b.b.cT.aA                                                                       P.c.aA.cT.b.b.kr.a                                    P.c.aA.cT.b.b.kr.aA                                                                       P.c.aA.kr.b.b.a.a                                                                         P.c.aA.kr.b.b.a.aA                                                                        P.c.aA.kr.b.b.m.a                         P.c.aA.kr.b.b.m.aA                                                                        P.c.aA.kr.b.b.ak.a                                                                        P.c.aA.kr.b.b.ak.aA                                   P.c.aA.kr.b.b.cP.a                                                                        P.c.aA.kr.b.b.cP.aA                                                                       P.c.aA.kr.b.b.cS.a                                    P.c.aA.kr.b.b.cS.aA                                                                       P.c.aA.kr.b.b.cT.a                                                                        P.c.aA.kr.b.b.cT.aA                                   P.c.aA.kr.b.b.kr.a                                                                        P.c.aA.kr.b.b.kr.aA                                                                       K.c.a.aw.b.b.aw.a                                     K.c.a.aw.b.b.aw.aA                                                                        K.c.aA.aw.b.b.aw.a                                                                        K.c.aA.aw.b.b.aw.aA                                   L.c.a.aw.b.b.aw.a                                                                         L.c.a.aw.b.b.aw.aA                                                                        L.c.aA.aw.b.b.aw.a                                    L.c.aA.aw.b.b.aw.aA                                              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                                                  P.c.a.aw.b.b.aw.aA                                    P.c.aA.aw.b.b.aw.a                                                                        P.c.aA.aw.b.b.aw.aA                                                                       Q.c.a.a.b.b.a.a                                                                           Q.c.a.a.b.b.a.aA                          Q.c.a.a.b.b.m.a                                                                           Q.c.a.a.b.b.m.aA                                                                          Q.c.a.a.b.b.ak.a                                                                          Q.c.a.a.b.b.ak.aA                         Q.c.a.a.b.b.cP.a                                                                          Q.c.a.a.b.b.cP.aA                                                                         Q.c.a.a.b.b.cS.a                                                                          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                                                                   Q.c.a.kr.b.b.m.aA                                                                         Q.c.a.kr.b.b.ak.a                                                                         Q.c.a.kr.b.b.ak.aA                        Q.c.a.krb.b.cP.a                                                                          Q.c.a.kr.b.b.cP.aA                                                                        Q.c.a.kr.b.b.cS.a                                                                         Q.c.a.kr.b.b.cS.aA                        Q.c.a.kr.b.b.cT.a                                                                         Q.c.a.kr.b.b.cT.aA                                                                        Q.c.a.kr.b.b.kr.a                                                                         Q.c.a.kr.b.b.kr.aA                        Q.c.aA.a.b.b.a.a                                                                        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               Q.c.aA.m.b.b.a.a                                                                          Q.c.aA.m.b.b.a.aA                                     Q.c.aA.m.b.b.m.a                                                                          Q.c.aA.m.b.b.m.aA                                                                         Q.c.aA.m.b.b.ak.a                                     Q.c.aA.m.b.b.ak.aA                                                                        Q.c.aA.m.b.b.cP.a                                                                         Q.c.aA.m.b.b.cP.aA                                    Q.c.aA.m.b.b.cS.a                                                                         Q.c.aA.m.b.b.cS.aA                                                                        Q.c.aA.m.b.b.cT.a                                     Q.c.aA.m.b.b.cT.aA                                                                        Q.c.aA.m.b.b.kr.a                                                                         Q.c.aA.m.b.b.kr.aA                                    Q.c.aA.ak.b.b.a.a                                                                         Q.c.aA.ak.b.b.a.aA                                                                        Q.c.aA.ak.b.b.m.a                                     Q.c.aA.ak.b.b.m.aA                                                                        Q.c.aA.ak.b.b.ak.a                                                                        Q.c.aA.ak.b.b.ak.aA                                   Q.c.aA.ak.b.b.cP.a                                                                        Q.c.aA.ak.b.b.cP.aA                                                                       Q.c.aA.ak.b.b.cS.a                                    Q.c.aA.ak.b.b.cS.aA                                                                       Q.c.aA.ak.b.b.cT.a                                                                        Q.c.aA.ak.b.b.cT.aA                                   Q.c.aA.ak.b.b.kr.a                                                                        Q.c.aA.ak.b.b.kr.aA                                                                       Q.c.aA.cP.b.b.a.a                                     Q.c.aA.cP.b.b.a.aA                                                                        Q.c.aA.cP.b.b.m.a                                                                         Q.c.aA.cP.b.b.m.aA                                    Q.c.aA.cP.b.b.ak.a                                                                        Q.c.aA.cP.b.b.ak.aA                                                                       Q.c.aA.cP.b.b.cP.a                                    Q.c.aA.cP.b.b.cP.aA                                                                       Q.c.aA.cP.b.b.cS.a                                                                        Q.c.aA.cP.b.b.cS.aA                                   Q.c.aA.cP.b.b.cT.a                                                                        Q.c.aA.cP.b.b.cT.aA                                                                       Q.c.aA.cP.b.b.kr.a                                    Q.c.aA.cP.b.b.kr.aA                                                                       Q.c.aA.cS.b.b.a.a                                                                         Q.c.aA.cS.b.b.a.aA                                    Q.c.aA.cS.b.b.m.a                                                                         Q.c.aA.cS.b.b.m.aA                                                                        Q.c.aA.cS.b.b.ak.a                                    Q.c.aA.cS.b.b.ak.aA                                                                       Q.c.aA.cS.b.b.cP.a                                                                        Q.c.aA.cS.b.b.cP.aA                                   Q.c.aA.cS.b.b.cS.a                                                                        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              Q.c.aA.kr.b.b.cP.aA                                                                       Q.c.aA.kr.b.b.cS.a                                                                        Q.c.aA.kr.b.b.cS.aA                                   Q.c.aA.kr.b.b.cT.a                                                                        Q.c.aA.kr.b.b.cT.aA                                                                       Q.c.aA.kr.b.b.kr.a                                    Q.c.aA.kr.b.b.kr.aA                                                                       R.c.a.a.b.b.a.a                                                                           R.c.a.a.b.b.a.aA                                                                          R.c.a.a.b.b.m.a                           R.c.a.a.b.b.m.aA                                                                          R.c.a.a.b.b.ak.a                                                                          R.c.a.a.b.b.ak.aA          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R.c.aA.cS.b.b.ak.aA                                                                       R.c.aA.cS.b.b.cP.a                                                                        R.c.aA.cS.b.b.cP.aA                                   R.c.aA.cS.b.b.cS.a                                                                        R.c.aA.cS.b.b.cS.aA                                                                       R.c.aA.cS.b.b.cT.a                                    R.c.aA.cS.b.b.cT.aA                                                                       R.c.aA.cS.b.b.kr.a                                                                        R.c.aA.cS.b.b.kr.aA                                   R.c.aA.cT.b.b.a.a                                                                         R.c.aA.cT.b.b.a.aA                                                                        R.c.aA.cT.b.b.m.a                                     R.c.aA.cT.b.b.m.aA                                               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S.c.a.a.b.b.a.aA                                                                          S.c.a.a.b.b.m.a                           S.c.a.a.b.b.m.aA                                                                          S.c.a.a.b.b.ak.a                                                                          S.c.a.a.b.b.ak.aA                                                                         S.c.a.a.b.b.cP.a                          S.c.a.a.b.b.cP.aA                                                                         S.c.a.a.b.b.cS.a                                                                          S.c.a.a.b.b.cS.aA                                                                         S.c.a.a.b.b.cT.a                          S.c.a.a.b.b.cT.aA                                                                         S.c.a.a.b.b.kr.a                                                                          S.c.a.a.b.b.kr.aA                                                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S.c.a.cS.b.b.cS.aA                                                                        S.c.a.cS.b.b.cT.a                         S.c.a.cS.b.b.cT.aA                                                                        S.c.a.cS.b.b.kr.a                                                                         S.c.a.cS.b.b.kr.aA                                                                        S.c.a.cT.b.b.a.a                          S.c.a.cT.b.b.a.aA                                                                         S.c.a.cT.b.b.m.a                                                                          S.c.a.cT.b.b.m.aA                                                                         S.c.a.cT.b.b.ak.a                         S.c.a.cT.b.b.ak.aA                                                                        S.c.a.cT.b.b.cP.a                                                                         S.c.a.cT.b.b.cP.aA                                                                        S.c.a.cT.b.b.cS.a                         S.c.a.cT.b.b.cS.aA                                                                        S.c.a.cT.b.b.cT.a                                                                         S.c.a.cT.b.b.cT.aA                                                                        S.c.a.cT.b.b.kr.a                         S.c.a.cT.b.b.kr.aA                                                                        S.c.a.kr.b.b.a.a                                                                          S.c.a.kr.b.b.a.aA                                                                         S.c.a.kr.b.b.m.a                          S.c.a.kr.b.b.m.aA                                                                         S.c.a.kr.b.b.ak.a                                                                         S.c.a.kr.b.b.ak.aA                                                                        S.c.a.kr.b.b.cP.a                         S.c.a.kr.b.b.cP.aA                                                                        S.c.a.kr.b.b.cS.a                                                                         S.c.a.kr.b.b.cS.aA                                                                        S.c.a.kr.b.b.cT.a                         S.c.a.kr.b.b.cT.aA                                                                        S.c.a.kr.b.b.kr.a                                                                         S.c.a.kr.b.b.kr.aA                                                                        S.c.aA.a.b.b.a.a                          S.c.aA.a.b.b.a.aA                                                                         S.c.aA.a.b.b.m.a                                                                          S.c.aA.a.b.b.m.aA                                                                         S.c.aA.a.b.b.ak.a                         S.c.aA.a.b.b.ak.aA                                                                        S.c.aA.a.b.b.cP.a                                                                         S.c.aA.a.b.b.cP.aA                                                                        S.c.aA.a.b.b.cS.a                         S.c.aA.a.b.b.cS.aA                                                                        S.c.aA.a.b.b.cT.a                                                                         S.c.aA.a.b.b.cT.aA                                                                        S.c.aA.a.b.b.kr.a                         S.c.aA.a.b.b.kr.aA                                                                        S.c.aA.m.b.b.a.a                                                                          S.c.aA.m.b.b.a.aA                                                                         S.c.aA.m.b.b.m.a                          S.c.aA.m.b.b.m.aA                                                                         S.c.aA.m.b.b.ak.a                                                                         S.c.aA.m.b.b.ak.aA                                    S.c.aA.m.b.b.cP.a                                                                         S.c.aA.m.b.b.cP.aA                                                                        S.c.aA.m.b.b.cS.a                                     S.c.aA.m.b.b.cS.aA                                                                        S.c.aA.m.b.b.cT.a                                                                         S.c.aA.m.b.b.cT.aA                                    S.c.aA.m.b.b.kr.a                                                                         S.c.aA.m.b.b.kr.aA                                                                        S.c.aA.ak.b.b.a.a                                     S.c.aA.ak.b.b.a.aA                                                                        S.c.aA.ak.b.b.m.a                                                                         S.c.aA.ak.b.b.m.aA                                    S.c.aA.ak.b.b.ak.a                                                                        S.c.aA.ak.b.b.ak.aA                                                                       S.c.aA.ak.b.b.cP.a                                    S.c.aA.ak.b.b.cP.aA                                                                       S.c.aA.ak.b.b.cS.a                                                                        S.c.aA.ak.b.b.cS.aA                                   S.c.aA.ak.b.b.cT.a                                                                        S.c.aA.ak.b.b.cT.aA                                                                       S.c.aA.ak.b.b.kr.a                                    S.c.aA.ak.b.b.kr.aA                                                                       S.c.aA.cP.b.b.a.a                                                                         S.c.aA.cP.b.b.a.aA                                                                        S.c.aA.cP.b.b.m.a                         S.c.aA.cP.b.b.m.aA                                                                        S.c.aA.cP.b.b.ak.a                                                                        S.c.aA.cP.b.b.ak.aA                                   S.c.aA.cP.b.b.cP.a                                                                        S.c.aA.cP.b.b.cP.aA                                                                       S.c.aA.cPh.b.cS.a                                     S.c.aA.cP.b.b.cS.aA                                                                       S.c.aA.cP.b.b.cT.a                                                                        S.c.aA.cP.b.b.cT.aA                                   S.c.aA.cP.b.b.kr.a                                                                        S.c.aA.cP.b.b.kr.aA                                                                       S.c.aA.cS.b.b.a.a                                                                         S.c.aA.cS.b.b.a.aA                        S.c.aA.cS.b.b.m.a                                                                         S.c.aA.cS.b.b.m.aA                                                                        S.c.aA.cS.b.b.ak.a                                    S.c.aA.cS.b.b.ak.aA                                                                       S.c.aA.cS.b.b.cP.a                                                                        S.c.aA.cS.b.b.cP.aA                                   S.c.aA.cS.b.b.cS.a                                                                        S.c.aA.cS.b.b.cS.aA                                                                       S.c.aA.cS.b.b.cT.a                                    S.c.aA.cS.b.b.cT.aA                                                                       S.c.aA.cS.b.b.kr.a                                                                        S.c.aA.cS.b.b.kr.aA                    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                            S.c.aA.cT.b.b.kr.aA                                                                       S.c.aA.kr.b.b.a.a                                                                         S.c.aA.kr.b.b.a.aA                                                                        S.c.aA.kr.b.b.m.a                         S.c.aA.kr.b.b.m.aA                                                                        S.c.aA.kr.b.b.ak.a                                                                        S.c.aA.kr.b.b.ak.aA                                   S.c.aA.kr.b.b.cP.a                                                                        S.c.aA.kr.b.b.cP.aA                                                                       S.c.aA.kr.b.b.cS.a                                    S.c.aA.kr.b.b.cS.aA                                                                       S.c.aA.kr.b.b.cT.a                                                                        S.c.aA.kr.b.b.cT.aA                                   S.c.aA.kr.b.b.kr.a                                                                        S.c.aA.kr.b.b.kr.aA                                                                       T.c.a.a.b.b.a.a                                                                           T.c.a.a.b.b.a.aA                          T.c.a.a.b.b.m.a                                                                           T.c.a.a.b.b.m.aA                                                                          T.c.a.a.b.b.ak.a                                                                          T.c.a.a.b.b.ak.aA                         T.c.a.a.b.b.cP.a                                                                          T.c.a.a.b.b.cP.aA                                                                         T.c.a.ab.b.cS.a                                                                           T.c.a.a.b.b.cS.aA                         T.c.a.a.b.b.cT.a                                                                          T.c.a.a.b.b.cT.aA                                                                         T.c.a.a.b.b.kr.a                                                                          T.c.a.a.b.b.kr.aA                         T.c.a.m.b.b.a.a                                                                           T.c.a.m.b.b.a.aA                                                                          T.c.a.m.b.b.m.a                                                                           T.c.a.m.b.b.m.aA                          T.c.a.m.b.b.ak.a                                                                          T.c.a.m.b.b.ak.aA                                                                         T.c.a.m.b.b.cP.a                                                                          T.c.a.m.b.b.cP.aA                         T.c.a.m.b.b.cS.a                                                                          T.c.a.m.b.b.cS.aA                                                                         T.c.a.m.b.b.cT.a                                                                          T.c.a.m.b.b.cT.aA                         T.c.a.m.b.b.kr.a                                                                          T.c.a.m.b.b.kr.aA                                                                         T.c.a.ak.b.b.a.a                                                                          T.c.a.ak.b.b.a.aA                         T.c.a.ak.b.b.m.a                                                                          T.c.a.ak.b.b.m.aA                                                                         T.c.a.ak.b.b.ak.a                                                                         T.c.a.ak.b.b.ak.aA                        T.c.a.ak.b.b.cP.a                                                                         T.c.a.ak.b.b.cP.aA                                                                        T.c.a.ak.b.b.cS.a                                                                         T.c.a.ak.b.b.cS.aA                        T.c.a.ak.b.b.cT.a                                                                         T.c.a.ak.b.b.cT.aA                                                                        T.c.a.ak.b.b.kr.a                                                                         T.c.a.ak.b.b.kr.aA                        T.c.a.cP.b.b.a.a                                                                          T.c.a.cP.b.b.a.aA                                                                         T.c.a.cP.b.b.m.a                                                                          T.c.a.cP.b.b.m.aA                         T.c.a.cP.b.b.ak.a                                                                         T.c.a.cP.b.b.ak.aA                                                                        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  T.c.a.cT.b.b.ak.a                                                                         T.c.a.cT.b.b.ak.aA                                                                        T.c.a.cT.b.b.cT.a                                                                         T.c.a.cT.b.b.cT.aA                        T.c.a.cT.b.b.cS.a                                                                         T.c.a.cT.b.b.cS.aA                                                                        T.c.a.cT.b.b.cT.a                                                                         T.c.a.cT.b.b.cT.aA                        T.c.a.cT.b.b.kr.a                                                                         T.c.a.cT.b.b.kr.aA                                                                        T.c.a.kr.b.b.a.a                                                                          T.c.a.kr.b.b.a.aA                         T.c.a.kr.b.b.m.a                                                                          T.c.a.kr.b.b.m.aA                                                                         T.c.a.kr.b.b.ak.a                                                                         T.c.a.kr.b.b.ak.aA                        T.c.a.kr.b.b.kr.a                                                                         T.c.a.kr.b.b.kr.aA                                                                        T.c.a.kr.b.b.kr.a                                                                         T.c.a.kr.b.b.kr.aA                        T.c.a.kr.b.b.cT.a                                                                         T.c.a.kr.b.b.cT.aA                                                                        T.c.a.kr.b.b.kr.a                                                                         T.c.a.kr.b.b.kr.aA                        T.c.Aa.a.b.b.a.a                                                                          T.c.Aa.a.b.b.a.aA                                                                         T.c.Aa.a.b.b.m.a                                                                          T.c.Aa.a.b.b.m.aA                         T.c.Aa.a.b.b.ak.a                                                                         T.c.Aa.a.b.b.ak.aA                                                                        T.c.Aa.a.b.b.cP.a                                     T.c.Aa.a.b.b.cP.aA                                                                        T.c.Aa.a.b.b.cS.a                                                                         T.c.Aa.a.b.b.cS.aA                                                                        T.c.Aa.a.b.b.cT.a                         T.c.Aa.a.b.b.cT.aA                                                                        T.c.Aa.a.b.b.kr.a                                                                         T.c.Aa.a.b.b.kr.aA                                                                        T.c.Aa.m.b.b.a.a                          T.c.Aa.m.b.b.a.aA                                                                         T.c.Aa.m.b.b.m.a                                                                          T.c.Aa.m.b.b.m.aA                                     T.c.Aa.m.b.b.ak.a                                                                         T.c.Aa.m.b.b.ak.aA                                                                        T.c.Aa.m.b.b.cP.a                                     T.c.Aa.m.b.b.cP.aA                                                                        T.c.Aa.m.b.b.cS.a                                                                         T.c.Aa.m.b.b.cS.aA                                    T.c.Aa.m.b.b.cT.a                                                                         T.c.Aa.m.b.b.cT.aA                                                                        T.c.Aa.m.b.b.kr.a                                     T.c.Aa.m.b.b.kr.aA                                                                        T.c.aA.ak.b.b.a.a                                                                         T.c.aA.ak.b.b.a.aA                                    T.c.aA.ak.b.b.m.a                                                                         T.c.aA.ak.b.b.m.aA                                                                        T.c.aA.ak.b.b.a.a                                     T.c.aA.ak.b.b.ak.aA                                                                       T.c.aA.ak.b.b.cP.a                                                                        T.c.aA.ak.b.b.cP.aA                                   T.c.aA.ak.b.b.cS.a                                                                        T.c.aA.ak.b.b.cS.aA                                                                       T.c.aA.ak.b.b.cT.a                                    T.c.aA.ak.b.b.cT.aA                                                                       T.c.aA.ak.b.b.kr.a                                                                        T.c.aA.ak.b.b.kr.aA                                   T.c.aA.cP.b.b.a.a                                                                         T.c.aA.cP.b.b.a.aA                                                                        T.c.aA.cP.b.b.m.a                                     T.c.aA.cP.b.b.m.aA                                                                        T.c.aA.cP.b.b.ak.a                                                                        T.c.aA.cP.b.b.ak.aA                                   T.c.aA.cP.b.b.cP.a                                                                        T.c.aA.cP.b.b.cP.aA                                                                       T.c.aA.cP.b.b.cS.a                                    T.c.aA.cP.b.b.cS.aA                                                                       T.c.aA.cP.b.b.cP.a                                                                        T.c.aA.cP.b.b.cT.aA                                   T.c.aA.cP.b.b.kr.a                                                                        T.c.aA.cP.b.b.kr.aA                                                                       T.c.aA.cS.b.b.a.a                                     T.c.aA.cS.b.b.a.aA                                                                        T.c.aA.cS.b.b.m.a                                                                         T.c.aA.cS.b.b.m.aA                                    T.c.aA.cS.b.b.ak.a                                                                        T.c.aA.cS.b.b.ak.aA                                                                       T.c.aA.cS.b.b.cP.a                                    T.c.aA.cS.b.b.cP.aA                                                                       T.c.aA.cS.b.b.cS.a                                                                        T.c.aA.cS.b.b.cS.aA                                   T.c.aA.cS.b.b.cT.a                                                                        T.c.aA.cS.b.b.cT.aA                                                                       T.c.aA.cS.b.b.kr.a                                    T.c.aA.cS.b.b.kr.aA                                                                       T.c.aA.cT.b.b.a.a                                                                         T.c.aA.cT.b.b.a.aA                                    T.c.aA.cT.b.b.m.a                                                                         T.c.aA.cT.b.b.m.aA                                                                        T.c.aA.cT.b.b.ak.a                                    T.c.aA.cT.b.b.ak.aA                                                                       T.c.aA.cT.b.b.cP.a                                                                        T.c.aA.cT.b.b.cP.aA                                   T.c.aA.cT.b.b.cS.a                                                                        T.c.aA.cT.b.b.cS.aA                                                                       T.c.aA.cT.b.b.cT.a                                    T.c.aA.cT.b.b.cT.aA                                                                       T.c.aA.cT.b.b.kr.a                                                                        T.c.aA.cT.b.b.kr.aA                                   T.c.aA.kr.b.b.a.a                                                                         T.c.aA.kr.b.b.a.aA                                                                        T.c.aA.kr.b.b.m.a                                     T.c.aA.kr.b.b.m.aA                                                                        T.c.aA.kr.b.b.ak.a                                                                        T.c.aA.kr.b.b.ak.aA                                   T.c.aA.kr.b.b.kr.a                                                                        T.c.aA.kr.b.b.kr.aA     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                                                                   U.c.a.a.b.b.cT.aA                                                                         U.c.a.a.b.b.kr.a                                                                          U.c.a.a.b.b.kr.aA                         U.c.a.m.b.b.a.a                                                                           U.c.a.m.b.b.a.aA                                                                          U.c.a.m.b.b.cP.a                                                                          U.c.a.m.b.b.cP.aA                         U.c.a.m.b.b.cS.a                                                                          U.c.a.m.b.b.cS.aA                                                                         U.c.a.m.b.b.cT.a                                                                          U.c.a.m.b.b.cT.aA                         U.c.a.m.b.b.kr.a                                                                          U.c.a.m.b.b.kr.aA                                                                         U.c.a.ak.b.b.a.a                                                                          U.c.a.ak.b.b.a.aA                         U.c.a.ak.b.b.cP.a                                                                         U.c.a.ak.b.b.cP.aA                                                                        U.c.a.ak.b.b.cS.a                                                                         U.c.a.ak.b.b.cS.aA                        U.c.a.ak.b.b.cT.a                                                                         U.c.a.ak.b.b.cT.aA                                                                        U.c.a.ak.b.b.kr.a                                                                         U.c.a.ak.b.b.kr.aA                        U.c.a.cP.b.b.a.a                                                                          U.c.a.cP.b.b.a.aA                                              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U.c.a.cT.b.b.cT.aA                        U.c.a.cT.b.b.kr.a                                                                         U.c.a.cT.b.b.kr.aA                                                                        U.c.a.kr.b.b.a.a                                                                          U.c.a.kr.b.b.a.aA                         U.c.a.kr.b.b.cP.a                                                                         U.c.a.kr.b.b.cP.aA                                                                        U.c.a.kr.b.b.cS.a                                                                         U.c.a.kr.b.b.cS.aA                        U.c.a.kr.b.b.cT.a                                                                         U.c.a.kr.b.b.cT.aA                                                                        U.c.a.kr.b.b.kr.a                                                                         U.c.a.kr.b.b.kr.aA                        U.c.aA.a.b.b.a.a                                                                          U.c.aA.a.b.b.a.aA                                                                         U.c.aA.a.b.b.cP.a                                                                         U.c.aA.a.b.b.cP.aA                        U.c.aA.a.b.b.cS.a                                                                         U.c.aA.a.b.b.cS.aA                                                                        U.c.aA.a.b.b.cT.a                                                                         U.c.aA.a.b.b.cT.aA                        U.c.aA.a.b.b.kr.a                                                                         U.c.aA.a.b.b.kr.aA                                                                        U.c.aA.m.b.b.a.a                                                                          U.c.aA.m.b.b.a.aA                         U.c.aA.m.b.b.cP.a                                                                         U.c.aA.m.b.b.cP.aA                                                                        U.c.aA.m.b.b.cS.a                                                                         U.c.aA.m.b.b.cS.aA                        U.c.aA.m.b.b.cT.a                                                                         U.c.aA.m.b.b.cT.aA                                                                        U.c.aA.m.b.b.kr.a                                                                         U.c.aA.m.b.b.kr.aA                        U.c.aA.ak.b.b.a.a                                                                         U.c.aA.ak.b.b.a.aA                                                                        U.c.aA.ak.b.b.cP.a                                                                        U.c.aA.ak.b.b.cP.aA                       U.c.aA.ak.b.b.cS.a                                                                        U.c.aA.ak.b.b.cS.aA                                                                       U.c.aA.ak.b.b.cT.a                                                                        U.c.aA.ak.b.b.cT.aA                       U.c.aA.ak.b.b.kr.a                                                                        U.c.aA.ak.b.b.kr.aA                                                                       U.c.aA.cP.b.b.a.a                                                                         U.c.aA.cP.b.b.a.aA                        U.c.aA.cP.b.b.cP.a                                                                        U.c.aA.cP.b.b.cP.aA                                                                       U.c.aA.cP.b.b.cS.a                                                                        U.c.aA.cP.b.b.cS.aA                       U.c.aA.cP.b.b.cT.a                                                                        U.c.aA.cP.b.b.cT.aA                                                                       U.c.aA.cP.b.b.kr.a                                                                        U.c.aA.cP.b.b.kr.aA                       U.c.aA.cS.b.b.a.a                                                                         U.c.aA.cS.b.b.a.aA                                                                        U.c.aA.cS.b.b.cP.a                                                                        U.c.aA.cS.b.b.cP.aA                       U.c.aA.cS.b.b.cS.a                                                                        U.c.aA.cS.b.b.cS.aA                                                                       U.c.aA.cS.b.b.cT.a                                                                        U.c.aA.cS.b.b.cT.aA                       U.c.aA.cS.b.b.kr.a                                                                        U.c.aA.cS.b.b.kr.aA                                                                       U.c.aA.cT.b.b.a.a                                                                         U.c.aA.cT.b.b.a.aA                        U.c.aA.cT.b.b.cP.a                                                                        U.c.aA.cT.b.b.cP.aA                                                                       U.c.aA.cT.b.b.cS.a                                                                        U.c.aA.cT.b.b.cS.aA                       U.c.aA.cT.b.b.cT.a                                                                        U.c.aA.cT.b.b.cT.aA                                                                       U.c.aA.cT.b.b.kr.a                                                                        U.c.aA.cT.b.b.kr.aA                       U.c.aA.kr.b.b.a.a                                                                         U.c.aA.kr.b.b.a.aA                                                                        U.c.aA.kr.b.b.cP.a                                                                        U.c.aA.kr.b.b.cP.aA                       U.c.aA.kr.b.b.cS.a                                                                        U.c.aA.kr.b.b.cS.aA                                                                       U.c.aA.kr.b.b.cT.a                                                                        U.c.aA.kr.b.b.cT.aA                       U.c.aA.kr.b.b.kr.a                                                                        V.c.a.a.b.b.a.a                                                                           V.c.a.a.b.b.a.aA                                                                          V.c.a.a.b.b.m.a                           V.c.a.a.b.b.m.aA                                                                          V.c.a.a.b.b.ak.a                                                                          V.c.a.a.b.b.ak.aA                                                                         V.c.a.a.b.b.cP.a                          V.c.a.a.b.b.cP.aA                                                                         V.c.a.a.b.b.cS.a                                                                          V.c.a.a.b.b.cS.aA                                                                         V.c.a.a.b.b.cT.a                          V.c.a.a.b.b.cT.aA                                                                         V.c.a.a.b.b.kr.a                                                                          V.c.a.a.b.b.kr.aA                                                                         V.c.a.m.b.b.a.a                           V.c.a.m.b.b.a.aA                                                                          V.c.a.m.b.b.m.a                                                                           V.c.a.m.b.b.m.aA                                                                          V.c.a.m.b.b.ak.a                          V.c.a.m.b.b.ak.aA                                                                         V.c.a.m.b.b.cP.a                                                                          V.c.a.m.b.b.cP.aA                                                                         V.c.a.m.b.b.cS.a                          V.c.a.m.b.b.cS.aA                                                                         V.c.a.m.b.b.cT.a                                                                          V.c.a.m.b.b.cT.aA                                                                         V.c.a.m.b.b.kr.a                          V.c.a.m.b.b.kr.aA                                                                         V.c.a.ak.b.b.a.a                                                                          V.c.a.ak.b.b.a.aA                                                                         V.c.a.ak.b.b.m.a                          V.c.a.ak.b.b.m.aA                                                                         V.c.a.ak.b.b.ak.a                                                                         V.c.a.ak.b.b.ak.aA                                                                        V.c.a.ak.b.b.cP.a                         V.c.a.ak.b.b.cP.aA                                                                        V.c.a.ak.b.b.cS.a                                                                         V.c.a.ak.b.b.cS.aA                                                                        V.c.a.ak.b.b.cT.a                         V.c.a.ak.b.b.cT.aA                                                                        V.c.a.ak.b.b.kr.a                                                                         V.c.a.ak.b.b.kr.aA                                                                        V.c.a.cP.b.b.a.a                          V.c.a.cP.b.b.a.aA                                                                         V.c.a.cP.b.b.m.a                                                                          V.c.a.cP.b.b.m.aA                                                                         V.c.a.cP.b.b.ak.a                         V.c.a.cP.b.b.ak.aA                                                                        V.c.a.cP.b.b.cP.a                                                                         V.c.a.cP.b.b.cP.aA                                                                        V.c.a.cP.b.b.cS.a                         V.c.a.cP.b.b.cS.aA                                                                        V.c.a.cP.b.b.cT.a                                                                         V.c.a.cP.b.b.cT.aA                                                                        V.c.a.cP.b.b.kr.a                         V.c.a.cP.b.b.kr.aA                                                                        V.c.a.cS.b.b.a.a                                                                          V.c.a.cS.b.b.a.aA                                                                         V.c.a.cS.b.b.m.a                          V.c.a.cS.b.b.m.aA                                                                         V.c.a.cS.b.b.ak.a                                                                         V.c.a.cS.b.b.ak.aA                                                                        V.c.a.cS.b.b.cP.a                         V.c.a.cS.b.b.cP.aA                                                                        V.c.a.cS.b.b.cS.a                                                                         V.c.a.cS.b.b.cS.aA                                                                        V.c.a.cS.b.b.cT.a                         V.c.a.cS.b.b.cT.aA                                                                        V.c.a.cS.b.b.kr.a                                                                         V.c.a.cS.b.b.kr.aA                                                                        V.c.a.cT.b.b.a.a                          V.c.a.cT.b.b.a.aA                                                                         V.c.a.cT.b.b.m.a                                                                          V.c.a.cT.b.b.m.aA                                                                         V.c.a.cT.b.b.ak.a                         V.c.a.cT.b.b.ak.aA                                                                        V.c.a.cT.b.b.cP.a                                                                         V.c.a.cT.b.b.cP.aA                                                                        V.c.a.cT.b.b.cS.a                         V.c.a.cT.b.b.cS.aA                                                                        V.c.a.cT.b.b.cT.a                                                                         V.c.a.cT.b.b.cT.aA                                                                        V.c.a.cT.b.b.kr.a                         V.c.a.cT.b.b.kr.aA                                                                        V.c.a.kr.b.b.a.a                                                                          V.c.a.kr.b.b.a.aA                                                                         V.c.a.kr.b.b.m.a                          V.c.a.kr.b.b.m.aA                                                                         V.c.a.kr.b.b.ak.a                                                                         V.c.a.kr.b.b.ak.aA                                                                        V.c.a.kr.b.b.cP.a                         V.c.a.kr.b.b.cP.aA                                                                        V.c.a.kr.b.b.cS.a                                                                         V.c.a.kr.b.b.cS.aA                                                                        V.c.a.kr.b.b.cT.a                         V.c.a.kr.b.b.cT.aA                                                                        V.c.a.kr.b.b.kr.a                                                                         V.c.a.kr.b.b.kr.aA                                                                        V.c.aA.a.b.b.a.a                          V.c.aA.a.b.b.a.aA                                                                         V.c.aA.a.b.b.m.a                                                                          V.c.aA.a.b.b.m.aA                                     V.c.aA.a.b.b.ak.a                                                                         V.c.aA.a.b.b.ak.aA                                                                        V.c.aA.a.b.b.cP.a                                     V.c.aA.a.b.b.cP.aA                                                                        V.c.aA.a.b.b.cS.a                                                                         V.c.aA.a.b.b.cS.aA                                    V.c.aA.a.b.b.cT.a                                                                         V.c.aA.a.b.b.cT.aA                                                                        V.c.aA.a.b.b.kr.a                                     V.c.aA.a.b.b.kr.aA                                                                        V.c.aA.m.b.b.a.a                                                                          V.c.aA.m.b.b.a.aA                                     V.c.aA.m.b.b.m.a                                                                          V.c.aA.m.b.b.m.aA                                                                         V.c.aA.m.b.b.ak.a                                     V.c.aA.m.b.b.ak.aA                                                                        V.c.aA.m.b.b.cP.a                                                                         V.c.aA.m.b.b.cP.aA                                    V.c.aA.m.b.b.cS.a                                                                         V.c.aA.m.b.b.cS.aA                                                                        V.c.aA.m.b.b.cT.a                                     V.c.aA.m.b.b.cT.aA                                                                        V.c.aA.m.b.b.kr.a                                                                         V.c.aA.m.b.b.kr.aA                                    V.c.aA.ak.b.b.a.a                                                                         V.c.aA.ak.b.b.a.aA                                                                        V.c.aA.ak.b.b.m.a                                     V.c.aA.ak.b.b.m.aA                                                                        V.c.aA.ak.b.b.ak.a                                                                        V.c.aA.ak.b.b.ak.aA                                   V.c.aA.ak.b.b.cP.a                                                                        V.c.aA.ak.b.b.cP.aA                                                                       V.c.aA.ak.b.b.cS.a                                    V.c.aA.ak.b.b.cS.aA                                                                       V.c.aA.ak.b.b.cT.a                                                                        V.c.aA.ak.b.b.cT.aA                                   V.c.aA.ak.b.b.kr.a                                                                        V.c.aA.ak.b.b.kr.aA                                                                       V.c.aA.cP.b.b.a.a                                     V.c.aA.cP.b.b.a.aA                                                                        V.c.aA.cP.b.b.m.a                                                                         V.c.aA.cP.b.b.m.aA                                    V.c.aA.cP.b.b.ak.a                                                                        V.c.aA.cP.b.b.ak.aA                                                                       V.c.aA.cP.b.b.cP.a                                    V.c.aA.cP.b.b.cP.aA                                                                       V.c.aA.cP.b.b.cS.a                                                                        V.c.aA.cP.b.b.cS.aA                                   V.c.aA.cP.b.b.cT.a                                                                        V.c.aA.cP.b.b.cT.aA                                                                       V.c.aA.cP.b.b.kr.a                                    V.c.aA.cP.b.b.kr.aA                                                                       V.c.aA.cS.b.b.a.a                                                                         V.c.aA.cS.b.b.a.aA                                    V.c.aA.cS.b.b.m.a                                                                         V.c.aA.cS.b.b.m.aA                                                                        V.c.aA.cS.b.b.ak.a                                    V.c.aA.cS.b.b.ak.aA                                                                       V.c.aA.cS.b.b.cP.a                                                                        V.c.aA.cS.b.b.cP.aA                                   V.c.aA.cS.b.b.cS.a                                                                        V.c.aA.cS.b.b.cS.aA                                                                       V.c.aA.cS.b.b.cT.a                                    V.c.aA.cS.b.b.cT.aA                                                                       V.c.aA.cS.b.b.kr.a                                                                        V.c.aA.cS.b.b.kr.aA                                   V.c.aA.cT.b.b.a.a                                                                         V.c.aA.cT.b.b.a.aA                                                                        V.c.aA.cT.b.b.m.a                                     V.c.aA.cT.b.b.m.aA                                                                        V.c.aA.cT.b.b.ak.a                                                                        V.c.aA.cT.b.b.ak.aA                                   V.c.aA.cT.b.b.cP.a                                                                        V.c.aA.cT.b.b.cP.aA                                                                       V.c.aA.cT.b.b.cS.a                                    V.c.aA.cT.b.b.cS.aA                                                                       V.c.aA.cT.b.b.cT.a                                                                        V.c.aA.cT.b.b.cT.aA                                   V.c.aA.cT.b.b.kr.a                                                                        V.c.aA.cT.b.b.kr.aA                                                                       V.c.aA.kr.b.b.a.a                                     V.c.aA.kr.b.b.a.aA                                                                        V.c.aA.kr.b.b.m.a                                                                         V.c.aA.kr.b.b.m.aA                                    V.c.aA.kr.b.b.ak.a                                                                        V.c.aA.kr.b.b.ak.aA                                                                       V.c.aA.kr.b.b.cP.a                                    V.c.aA.kr.b.b.cP.aA                                                                       V.c.aA.kr.b.b.cS.a                                                                        V.c.aA.kr.b.b.cS.aA                                   V.c.aA.kr.b.b.cT.a                                                                        V.c.aA.kr.b.b.cT.aA                                                                       V.c.aA.kr.b.b.kr.a                                    V.c.aA.kr.b.b.kr.aA                                                                       W.c.a.a.b.b.a.a                                                                           W.c.a.a.b.b.a.aA                                                                          W.c.a.a.b.b.m.a                           W.c.a.a.b.b.m.aA                                                                          W.c.a.a.b.b.ak.a                                                                          W.c.a.a.b.b.ak.aA                                                                         W.c.a.a.b.b.cP.a                          W.c.a.a.b.b.cP.aA                                                                         W.c.a.a.b.b.cS.a                                                                          W.c.a.a.b.b.cS.aA                                                                         W.c.a.a.b.b.cT.a                          W.c.a.a.b.b.cT.aA                                                                         W.c.a.a.b.b.kr.a                                                                          W.c.a.a.b.b.kr.aA                                                                         W.c.a.m.b.b.a.a                           W.c.a.m.b.b.a.aA                                                                          W.c.a.m.b.b.m.a                                                                           W.c.a.m.b.b.m.aA                                      W.c.a.m.b.b.ak.a                                                                          W.c.a.m.b.b.ak.aA                                                                         W.c.a.m.b.b.cP.a                                      W.c.a.m.b.b.cP.aA                                                                         W.c.a.m.b.b.cS.a                                                                          W.c.a.m.b.b.cS.aA                                     W.c.a.m.b.b.cT.a                                                                          W.c.a.m.b.b.cT.aA                                                                         W.c.a.m.b.b.kr.a                                      W.c.a.m.b.b.kr.aA                                                                         W.c.a.ak.b.b.a.a                                                                          W.c.a.ak.b.b.a.aA                                                                         W.c.a.ak.b.b.m.a                          W.c.a.ak.b.b.m.aA                                                                         W.c.a.ak.b.b.ak.a                                                                         W.c.a.ak.b.b.ak.aA                                    W.c.a.ak.b.b.cP.a                                                                         W.c.a.ak.b.b.cP.aA                                                                        W.c.a.ak.b.b.cS.a                                     W.c.a.ak.b.b.cS.aA                                                                        W.c.a.ak.b.b.cT.a                                                                         W.c.a.ak.b.b.cT.aA                                    W.c.a.ak.b.b.kr.a                                                                         W.c.a.ak.b.b.kr.aA                                                                        W.c.a.cP.b.b.a.a                                                                          W.c.a.cP.b.b.a.aA                         W.c.a.cP.b.b.m.a                                                                          W.c.a.cP.b.b.m.aA                                                                         W.c.a.cP.b.b.ak.a                                     W.c.a.cP.b.b.ak.aA                                                                        W.c.a.cP.b.b.cP.a                                                                         W.c.a.cP.b.b.cP.aA                                    W.c.a.cP.b.b.cS.a                                                                         W.c.a.cP.b.b.cS.aA                                                                        W.c.a.cP.b.b.cT.a                                     W.c.a.cP.b.b.cT.aA                                                                        W.c.a.cP.b.b.kr.a                                                                         W.c.a.cP.b.b.kr.aA                                                                        W.c.a.cS.b.b.a.a                          W.c.a.cS.b.b.a.aA                                                                         W.c.a.cS.b.b.m.a                                                                          W.c.a.cS.b.b.m.aA                                     W.c.a.cS.b.b.ak.a                                                                         W.c.a.cS.b.b.ak.aA                                                                        W.c.a.cS.b.b.cP.a                                     W.c.a.cS.b.b.cP.aA                                                                        W.c.a.cS.b.b.cS.a                                                                         W.c.a.cS.b.b.cS.aA                                    W.c.a.cS.b.b.cT.a                                                                         W.c.a.cS.b.b.cT.aA                                                                        W.c.a.cS.b.b.kr.a                                     W.c.a.cS.b.b.kr.aA                                                                        W.c.a.cT.b.b.a.a                                                                          W.c.a.cT.b.b.a.aA                                                                         W.c.a.cT.b.b.m.a                          W.c.a.cT.b.b.m.aA                                                                         W.c.a.cT.b.b.ak.a                                                                         W.c.a.cT.b.b.ak.aA                                    W.c.a.cT.b.b.cP.a                                                                         W.c.a.cT.b.b.cP.aA                                                                        W.c.a.cT.b.b.cS.a                                     W.c.a.cT.b.b.cS.aA                                                                        W.c.a.cT.b.b.cT.a                                                                         W.c.a.cT.b.b.cT.aA                                    W.c.a.cT.b.b.kr.a                                                                         W.c.a.cT.b.b.kr.aA                                                                        W.c.a.kr.b.b.a.a                                                                          W.c.a.kr.b.b.a.aA                         W.c.a.kr.b.b.m.a                                                                          W.c.a.kr.b.b.m.aA                                                                         W.c.a.kr.b.b.ak.a                                     W.c.a.kr.b.b.ak.aA                                                                        W.c.a.kr.b.b.cP.a                                                                         W.c.a.kr.b.b.cP.aA                                    W.c.a.kr.b.b.cS.a                                                                         W.c.a.kr.b.b.cS.aA                                                                        W.c.a.kr.b.b.cT.a                                     W.c.a.kr.b.b.cT.aA                                                                        W.c.a.kr.b.b.kr.a                                                                         W.c.a.kr.b.b.kr.aA                                                                        W.c.aA.a.b.b.a.a                          W.c.aA.a.b.b.a.aA                                                                         W.c.aA.a.b.b.m.a                                                                          W.c.aA.a.b.b.m.aA                                     W.c.aA.a.b.b.ak.a                                                                         W.c.aA.a.b.b.ak.aA                                                                        W.c.aA.a.b.b.cP.a                                     W.c.aA.a.b.b.cP.aA                                                                        W.c.aA.a.b.b.cS.a                                                                         W.c.aA.a.b.b.cS.aA                                    W.c.aA.a.b.b.cT.a                                                                         W.c.aA.a.b.b.cT.aA                                                                        W.c.aA.a.b.b.kr.a                                     W.c.aA.a.b.b.kr.aA                                                                        W.c.aA.m.b.b.a.a                                                                          W.c.aA.m.b.b.a.aA                                     W.c.aA.m.b.b.m.a                                                                          W.c.aA.m.b.b.m.aA                                                                         W.c.aA.m.b.b.ak.a                                     W.c.aA.m.b.b.ak.aA                                                                        W.c.aA.m.b.b.cP.a                                                                         W.c.aA.m.b.b.cP.aA                                    W.c.aA.m.b.b.cS.a                                                                         W.c.aA.m.b.b.cS.aA                                                                        W.c.aA.m.b.b.cT.a                                     W.c.aA.m.b.b.cT.aA                                                                        W.c.aA.m.b.b.kr.a                                                                         W.c.aA.m.b.b.kr.aA                                                                        W.c.aA.ak.b.b.a.a                         W.c.aA.ak.b.b.a.aA                                                                        W.c.aA.ak.b.b.m.a                                                                         W.c.aA.ak.b.b.m.aA                                    W.c.aA.ak.b.b.ak.a                                                                        W.c.aA.ak.b.b.ak.aA                                                                       W.c.aA.ak.b.b.cP.a                                    W.c.aA.ak.b.b.cP.aA                                                                       W.c.aA.ak.b.b.cS.a                                                                        W.c.aA.ak.b.b.cS.aA                                   W.c.aA.ak.b.b.cT.a                                                                        W.c.aA.ak.b.b.cT.aA                                                                       W.c.aA.ak.b.b.kr.a                                    W.c.aA.ak.b.b.kr.aA                                                                       W.c.aA.cP.b.b.a.a                                                                         W.c.aA.cP.b.b.a.aA                                    W.c.aA.cP.b.b.m.a                                                                         W.c.aA.cP.b.b.m.aA                                                                        W.c.aA.cP.b.b.ak.a                                    W.c.aA.cP.b.b.ak.aA                                                                       W.c.aA.cP.b.b.cP.a                                                                        W.c.aA.cP.b.b.cP.aA                                   W.c.aA.cP.b.b.cS.a                                                                        W.c.aA.cP.b.b.cS.aA                                                                       W.c.aA.cP.b.b.cT.a                                    W.c.aA.cP.b.b.cT.aA                                                                       W.c.aA.cP.b.b.kr.a                                                                        W.c.aA.cP.b.b.kr.aA                                                                       W.c.aA.cS.b.b.a.a                         W.c.aA.cS.b.b.a.aA                                                                        W.c.aA.cS.b.b.m.a                                                                         W.c.aA.cS.b.b.m.aA                                    W.c.aA.cS.b.b.ak.a                                                                        W.c.aA.cS.b.b.ak.aA                                                                       W.c.aA.cS.b.b.cP.a                                    W.c.aA.cS.b.b.cP.aA                                                                       W.c.aA.cS.b.b.cS.a                                                                        W.c.aA.cS.b.b.cS.aA                                   W.c.aA.cS.b.b.cT.a                                                                        W.c.aA.cS.b.b.cT.aA                                                                       W.c.aA.cS.b.b.kr.a                                    W.c.aA.cS.b.b.kr.aA                                                                       W.c.aA.cT.b.b.a.a                                                                         W.c.aA.cT.b.b.a.aA                                    W.c.aA.cT.b.b.m.a                                                                         W.c.aA.cT.b.b.m.aA                                                                        W.c.aA.cT.b.b.ak.a                                    W.c.aA.cT.b.b.ak.aA                                                                       W.c.aA.cT.b.b.cP.a                                                                        W.c.aA.cT.b.b.cP.aA                                   W.c.aA.cT.b.b.cS.a                                                                        W.c.aA.cT.b.b.cS.aA                                                                       W.c.aA.cT.b.b.cT.a                                    W.c.aA.cT.b.b.cT.aA                                                                       W.c.aA.cT.b.b.kr.a                                                                        W.c.aA.cT.b.b.kr.aA                                   W.c.aA.kr.b.b.a.a                                                                         W.c.aA.kr.b.b.a.aA                                                                        W.c.aA.kr.b.b.m.a                                     W.c.aA.kr.b.b.m.aA                                                                        W.c.aA.kr.b.b.ak.a                                                                        W.c.aA.kr.b.b.ak.aA                                   W.c.aA.kr.b.b.cP.a                                                                        W.c.aA.kr.b.b.cP.aA                                                                       W.c.aA.kr.b.b.cS.a                                    W.c.aA.kr.b.b.cS.aA                                                                       W.c.aA.kr.b.b.cT.a                                                                        W.c.aA.kr.b.b.cT.aA                                   W.c.aA.kr.b.b.kr.a                                                                        W.c.aA.kr.b.b.kr.aA                                                                       Y.c.a.a.b.b.a.a                                                                           Y.c.a.a.b.b.a.aA                          Y.c.a.a.b.b.m.a                                                                           Y.c.a.a.b.b.m.aA                                                                          Y.c.a.a.b.b.ak.a                                                                          Y.c.a.a.b.b.ak.aA                         Y.c.a.a.b.b.cP.a                                                                          Y.c.a.a.b.b.cP.aA                                                                         Y.c.a.a.b.b.cS.a                                                                          Y.c.a.a.b.b.cS.aA                         Y.c.a.a.b.b.cT.a                                                                          Y.c.a.a.b.b.cT.aA                                                                         Y.c.a.a.b.b.kr.a                                                                          Y.c.a.a.b.b.kr.aA                         Y.c.a.m.b.b.a.a                                                                           Y.c.a.m.b.b.a.aA                                                                          Y.c.a.m.b.b.m.a                                                                           Y.c.a.m.b.b.m.aA                          Y.c.a.m.b.b.ak.a                                                                          Y.c.a.m.b.b.ak.aA                                                                         Y.c.a.m.b.b.cP.a                                                                          Y.c.a.m.b.b.cP.aA                         Y.c.a.m.b.b.cS.a                                                                          Y.c.a.m.b.b.cS.aA                                                                         Y.c.a.m.b.b.cT.a                                                                          Y.c.a.m.b.b.cT.aA                         Y.c.a.m.b.b.kr.a                                                                          Y.c.a.m.b.b.kr.aA                                                                         Y.c.a.ak.b.b.a.a                                                                          Y.c.a.ak.b.b.a.aA                         Y.c.a.ak.b.b.m.a                                                                          Y.c.a.ak.b.b.m.aA                                                                         Y.c.a.ak.b.b.ak.a                                                                         Y.c.a.ak.b.b.ak.aA                        Y.c.a.ak.b.b.cP.a                                                                         Y.c.a.ak.b.b.cP.aA                                                                        Y.c.a.ak.b.b.cS.a                                                                         Y.c.a.ak.b.b.cS.aA                        Y.c.a.ak.b.b.cT.a                                                                         Y.c.a.ak.b.b.cT.aA                                                                        Y.c.a.ak.b.b.kr.a                                                                         Y.c.a.ak.b.b.kr.aA                        Y.c.a.cP.b.b.a.a                                                                          Y.c.a.cP.b.b.a.aA                                                                         Y.c.a.cP.b.b.m.a                                                                          Y.c.a.cP.b.b.m.aA                         Y.c.a.cP.b.b.ak.a                                                                         Y.c.a.cP.b.b.ak.aA                                                                        Y.c.a.cP.b.b.cP.a                                                                         Y.c.a.cP.b.b.cP.aA                        Y.c.a.cP.b.b.cS.a                                                                         Y.c.a.cP.b.b.cS.aA                                                                        Y.c.a.cP.b.b.cT.a                                                                         Y.c.a.cP.b.b.cT.aA                        Y.c.a.cP.b.b.kr.a                                                                         Y.c.a.cP.b.b.kr.aA                                                                        Y.c.a.cS.b.b.a.a                                                                          Y.c.a.cS.b.b.a.aA                         Y.c.a.cS.b.b.m.a                                                                          Y.c.a.cS.b.b.m.aA                                                                         Y.c.a.cS.b.b.ak.a                                                                         Y.c.a.cS.b.b.ak.aA                        Y.c.a.cS.b.b.cP.a                                                                         Y.c.a.cS.b.b.cP.aA                                                                        Y.c.a.cS.b.b.cS.a                                                                         Y.c.a.cS.b.b.cS.aA                        Y.c.a.cS.b.b.cT.a                                                                         Y.c.a.cS.b.b.cT.aA                                                                        Y.c.a.cS.b.b.kr.a                                                                         Y.c.a.cS.b.b.kr.aA                        Y.c.a.cT.b.b.a.a                                                                          Y.c.a.cT.b.b.a.aA                                                                         Y.c.a.cT.b.b.m.a                                                                          Y.c.a.cT.b.b.m.aA                         Y.c.a.cT.b.b.ak.a                                                                         Y.c.a.cT.b.b.ak.aA                                                                        Y.c.a.cT.b.b.cP.a                                                                         Y.c.a.cT.b.b.cP.aA                        Y.c.a.cT.b.b.cS.a                                                                         Y.c.a.cT.b.b.cS.aA                                                                        Y.c.a.cT.b.b.cT.a                                                                         Y.c.a.cT.b.b.cT.aA                        Y.c.a.cT.b.b.kr.a                                                                         Y.c.a.cT.b.b.kr.aA                                                                        Y.c.a.kr.b.b.a.a                                                                          Y.c.a.kr.b.b.a.aA                         Y.c.a.kr.b.b.m.a                                                                          Y.c.a.kr.b.b.m.aA                                                                         Y.c.a.kr.b.b.ak.a                                                                         Y.c.a.kr.b.b.ak.aA                        Y.c.a.kr.b.b.cP.a                                                                         Y.c.a.kr.b.b.cP.aA                                                                        Y.c.a.kr.b.b.cS.a                                                                         Y.c.a.kr.b.b.cS.aA                        Y.c.a.kr.b.b.cT.a                                                                         Y.c.a.kr.b.b.cT.aA                                                                        Y.c.a.kr.b.b.kr.a                                                                         Y.c.a.kr.b.b.kr.aA                        Y.c.aA.a.b.b.a.a                                                                          Y.c.aA.a.b.b.a.aA                                                                         Y.c.aA.a.b.b.m.a                                                                          Y.c.aA.a.b.b.m.aA                         Y.c.aA.a.b.b.ak.a                                                                         Y.c.aA.a.b.b.ak.aA                                                                        Y.c.aA.a.b.b.cP.a                                     Y.c.aA.a.b.b.cP.aA                                                                        Y.c.aA.a.b.b.cS.a                                                                         Y.c.aA.a.b.b.cS.aA                                                                        Y.c.aA.a.b.b.cT.a                         Y.c.aA.a.b.b.cT.aA                                                                        Y.c.aA.a.b.b.kr.a                                                                         Y.c.aA.a.b.b.kr.aA                                                                        Y.c.aA.m.b.b.a.a                          Y.c.aA.m.b.b.a.aA                                                                         Y.c.aA.m.b.b.m.a                                                                          Y.c.aA.m.b.b.m.aA                                     Y.c.aA.m.b.b.ak.a                                                                         Y.c.aA.m.b.b.ak.aA                                                                        Y.c.aA.m.b.b.cP.a                                     Y.c.aA.m.b.b.cP.aA                                                                        Y.c.aA.m.b.b.cS.a                                                                         Y.c.aA.m.b.b.cS.aA                                    Y.c.aA.m.b.b.cT.a                                                                         Y.c.aA.m.b.b.cT.aA                                                                        Y.c.aA.m.b.b.kr.a                                     Y.c.aA.m.b.b.kr.aA                                                                        Y.c.aA.ak.b.b.a.a                                                                         Y.c.aA.ak.b.b.a.aA                                    Y.c.aA.ak.b.b.m.a                                                                         Y.c.aA.ak.b.b.m.aA                                                                        Y.c.aA.ak.b.b.ak.a                                    Y.c.aA.ak.b.b.ak.aA                                                                       Y.c.aA.ak.b.b.cP.a                                                                        Y.c.aA.ak.b.b.cP.aA                                   Y.c.aA.ak.b.b.cS.a                                                                        Y.c.aA.ak.b.b.cS.aA                                                                       Y.c.aA.ak.b.b.cT.a                                    Y.c.aA.ak.b.b.cT.aA                                                                       Y.c.aA.ak.b.b.kr.a                                                                        Y.c.aA.ak.b.b.kr.aA                                   Y.c.aA.cP.b.b.a.a                                                                         Y.c.aA.cP.b.b.a.aA                                                                        Y.c.aA.cP.b.b.m.a                                     Y.c.aA.cP.b.b.m.aA                                                                        Y.c.aA.cP.b.b.ak.a                                                                        Y.c.aA.cP.b.b.ak.aA                                   Y.c.aA.cP.b.b.cP.a                                                                        Y.c.aA.cP.b.b.cP.aA                                                                       Y.c.aA.cP.b.b.cS.a                                    Y.c.aA.cP.b.b.cS.aA                                                                       Y.c.aA.cP.b.b.cT.a                                                                        Y.c.aA.cP.b.b.cT.aA                                   Y.c.aA.cP.b.b.kr.a                                                                        Y.c.aA.cP.b.b.kr.aA                                                                       Y.c.aA.cS.b.b.a.a                                     Y.c.aA.cS.b.b.a.aA                                                                        Y.c.aA.cS.b.b.m.a                                                                         Y.c.aA.cS.b.b.m.aA                                    Y.c.aA.cS.b.b.ak.a                                                                        Y.c.aA.cS.b.b.ak.aA                                                                       Y.c.aA.cS.b.b.cP.a                                    Y.c.aA.cS.b.b.cP.aA                                                                       Y.c.aA.cS.b.b.cS.a                                                                        Y.c.aA.cS.b.b.cS.aA                                   Y.c.aA.cS.b.b.cT.a                                                                        Y.c.aA.cS.b.b.cT.aA                                                                       Y.c.aA.cS.b.b.kr.a                                    Y.c.aA.cS.b.b.kr.aA                                                                       Y.c.aA.cT.b.b.a.a                                                                         Y.c.aA.cT.b.b.a.aA                                    Y.c.aA.cT.b.b.m.a                                                                         Y.c.aA.cT.b.b.m.aA                                                                        Y.c.aA.cT.b.b.ak.a                                    Y.c.aA.cT.b.b.ak.aA                                                                       Y.c.aA.cT.b.b.cP.a                                                                        Y.c.aA.cT.b.b.cP.aA                                   Y.c.aA.cT.b.b.cS.a                                                                        Y.c.aA.cT.b.b.cS.aA                                                                       Y.c.aA.cT.b.b.cT.a                                    Y.c.aA.cT.b.b.cT.aA                                                                       Y.c.aA.cT.b.b.kr.a                                                                        Y.c.aA.cT.b.b.kr.aA                                   Y.c.aA.kr.b.b.a.a                                                                         Y.c.aA.kr.b.b.a.aA                                                                        Y.c.aA.kr.b.b.m.a                                     Y.c.aA.kr.b.b.m.aA                                                                        Y.c.aA.kr.b.b.ak.a                                                                        Y.c.aA.kr.b.b.ak.aA                                   Y.c.aA.kr.b.b.cP.a                                                                        Y.c.aA.kr.b.b.cP.aA                                                                       Y.c.aA.kr.b.b.cS.a                                    Y.c.aA.kr.b.b.cS.aA                                                                       Y.c.aA.kr.b.b.cT.a                                                                        Y.c.aA.kr.b.b.cT.aA                                   Y.c.aA.kr.b.b.kr.a                                                                        Y.c.aA.kr.b.b.kr.aA                                               __________________________________________________________________________

Pharmaceutical Formulations and Administration.

Another aspect of the invention relates to compositions comprisingcompound(s) of this invention plus one or morepharmaceutically-acceptable carriers. One or more compounds of theinvention (herein referred to as the active ingredients) areadministered by any route appropriate to the condition to be treated.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary with,for example, the condition of the recipient.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural) administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Techniques and formulations generally are foundin Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton,Pa.) which is incorporated by reference herein. Such methods include thestep of bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration areprepared as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally are coated or scored and optionally areformulated so as to provide slow or controlled release of the activeingredient therefrom.

For administration to the eye or other external tissues e.g. mouth andskin, the formulations are preferably applied as a topical ointment orcream if; containing the active ingredient(s) in an amount of, forexample, 0.075 to 20% w/w (including active ingredient(s) in a rangebetween 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10%w/w. When formulated in an ointment, the active ingredients may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus the cream should preferably be anon-greasy, non-staining and washable product with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for nasal administration wherein the carrier is asolid include a coarse powder having a particle size for example in therange 20 to 500 microns (including particle sizes in a range between 20and 500 microns in increments of 5 microns such as 30 microns, 35microns, etc.), which is administered by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as for example a nasal spray or as nasal drops, includeaqueous or oily solutions of the active ingredient. Formulationssuitable for aerosol administration may be prepared according toconventional methods and may be delivered with other therapeutic agents.

Formulations suitable for inhalation therapy are prepared as aerosols orpowders having a particle size small enough to dose the alveoli. Suchpowders and aerosols are prepared by any of the methods common in theart. Ordinarily aerosols are aqueous aerosols.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention are used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention ("controlled release formulations") in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient.

Effective dose of active ingredient depends on the nature of thecondition being treated, the method of treatment, pharmaceuticalformulation, and the like. It can be expected to be from about 0.001 toabout 30 mg/kg body weight per day. Particular dose ranges aredetermined by the methods common in the art. Such methods include doseescalation studies involving animal models such as SIV in monkeys or HIVIN SCID mouse systems. Studies of this type take into accounteffectiveness and toxicity of a particular dose among other variablescommonly studied in the art.

Active ingredients of the invention are also used in combination withother active ingredients heretofore employed or useful in the treatmentof HIV, including nucleotide or nucleoside analogues such as PMEA, PMPA,PMEDAP, PMPDAP, DDI, AZT, DDC, D4T, D4AP, bis(POM) PMEA and the like.Such combinations are selected based on the condition to be treated,cross-reactivities of ingredients and pharmaco-properties of thecombination.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein, to the extent suchproducts are novel and unobvious over the prior art. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes novel andunobvious compounds produced by a process comprising contacting acompound of structure I, II, or III with a mammal for a period of timesufficient to yield a metabolic product of the compound. Such productstypically are identified by preparing a radiolabeled (e.g. C¹⁴ or H³)compound of structure I, II, or III, administering it parenterally in adetectable dose (e.g. greater than about 0.5 mg/kg) to an animal such asrat, mouse, guinea pig, monkey, or to man, allowing sufficient time formetabolism to occur (typically about 30 seconds to 30 hours) andisolating its conversion products from the urine, blood or otherbiological samples. These products are easily isolated since they arelabeled (others are isolated by the use of antibodies capable of bindingepitopes surviving in the metabolite). The metabolite structures aredetermined in conventional fashion, e.g. by MS or NMR analysis. Ingeneral, analysis of metabolites is done in the same way as conventionaldrug metabolism studies well-known to those skilled in the art. Theconversion products, so long as they are not otherwise found in vivo,are useful in diagnostic assays for therapeutic dosing of the compoundsof structure I, II, or III--even if they possess no HIV proteaseinhibitory activity of their own. Particular compounds are products ofcytochrome-mediated oxidation. These include oxidation of aryl groups tophenolic groups and amino to hydroxyl. They are identified by incubatingthe compounds described herein with liver cytochrome preparations inconventional fashion.

Immunogens Antibodies, and Assays.

The compounds of this invention, or the biologically active substancesproduced from these compounds by hydrolysis or metabolism in vivo, areused as immunogens to prepare antibodies capable of binding specificallyto the compounds or their metabolic products which retainimmunologically recognized epitopes (sites of antibody binding). Theimmunogenic compositions therefore are useful as intermediates in thepreparation of antibodies for use in diagnostic, quality control, or thelike methods or in assays for the compounds or their novel metabolicproducts.

The hydrolysis products of interest include products of the hydrolysisof protected acidic groups (such as carboxylic acids and phenols),hydroxy groups, and basic groups (such as amines). The metabolicproducts described above may retain a substantial degree ofimmunological cross reactivity with the compounds of the invention.Thus, the antibodies of this invention will be capable of binding to theinhibitor compounds of the invention without binding to thenon-inhibitory protected compounds; alternatively the metabolicproducts, will be capable of binding to the non-inhibitory protectedcompounds and/or the metabolitic products without binding to theinhibitory compounds of the invention, or will be capable of bindingspecifically to any one or all three. The antibodies desirably will notsubstantially cross-react with naturally-occurring materials (other thannaturally produced metabolites as discussed above). Substantialcross-reactivity is reactivity under specific assay conditions forspecific analytes such that it interferes with the assay results.

The immunogens of this invention contain the compound presenting thedesired epitope in association with an immunogenic substance such as anantigenic polypeptide. Within the context of the invention suchassociation means covalent bonding to form an immunogenic conjugate(when applicable) or a mixture of non-covalently bonded materials, or acombination of the above. Immunogenic substances include adjuvants suchas Freund's adjuvant, immunogenic proteins such as viral, bacterial,yeast, plant and animal polypeptides, in particular keyhole limpethemocyanin, serum albumin, bovine thyroglobulin or soybean trypsininhibitor, and immunogenic polysaccharides. Typically, the compoundhaving the structure of the desired epitope is covalently conjugated toan immunogenic polypeptide or polysaccharide by the use of apolyfunctional (ordinarily bifunctional) cross-linking agent. Methodsfor the manufacture of hapten immunogens are conventional per se and anyof the methods used heretofore for conjugating haptens to immunogenicpolypeptides or the like are suitably employed here as well, taking intoaccount the functional groups on the precursors or hydrolytic productswhich are available for cross-linking and the likelihood of producingantibodies specific to the epitope in question as opposed to theimmunogenic substance.

Typically the polypeptide is conjugated to a site on the compound of theinvention distant from the epitope to be recognized.

The conjugates are prepared in conventional fashion. For example, thecross-linking agents N-hydroxysuccinimide, succinic anhydride oralkN=C=Nalk are useful in preparing the conjugates of this invention.The conjugates comprise a compound of the invention attached by a bondor a linking group of 1-100, typically, 1-25, more typically 1-10 carbonatoms to the immunogenic substance. The conjugates are separated fromstarting materials and by products using chromatography or the like, andthen are sterile filtered and vialed for storage.

The compounds of this invention are cross-linked for example through anyone or more of the following groups: a hydroxyl group of E, G, J, L, T,or U; a carboxyl group of E, G, T, or T; a carbon atom of the compoundof formulas I, II, or III in substitution of H and/or an amine group ofE, G, J, L, T, or U.

Animals are typically immunized against the immunogenic conjugates orderivatives by combining 1 mg or 1 μg of conjugate (for rabbits or mice,respectively) with 3 volumes of Freund's complete adjuvant and injectingthe solution intradermally at multiple sites. One month later theanimals are boosted with 1/5 to 1/10 the original amount of conjugate inFreund's complete adjuvant (or other suitable adjuvant) by subcutaneousinjection at multiple sites. 7 to 14 days later animals are bled and theserum is assayed for the desired antibody titer. Animals are boosteduntil the titer plateaus. Preferably, the animal is boosted with theconjugate in which the precursor or product is linked to a differentprotein, through a different cross-linking agent or both. Optionally,aggregating agents such as alum are used to enhance the immune response.

After immunization, monoclonal antibodies are prepared by recoveringimmune lymphoid cells (typically spleen cells or lymphocytes from lymphnode tissue) from immunized animals and immortalizing the cells inconventional fashion, e.g., by fusion with myeloma cells or byEpstein-Barr virus transformation and screening for clones expressingthe desired antibody. The hybridoma technique described originally beKohler and Milstein, Eur. T. Immunol. (1976) 6:511 has been widelyapplied to produce hybrid cell lines that secrete high levels ofmonoclonal antibodies against many specific antigens.

It is possible to fuse cells of one species with another. However, it ispreferably that the source of the immunized antibody producing cells andthe myeloma be from the same species.

The hybrid cell lines are maintained in culture in vitro. The cell linesof this invention are selected or maintained in ahypoxanthine-aminopterin thymidine (HAT) medium. However, theestablished hybridoma cell line can be maintained on a variety ofnutritionally adequate media. The secreted antibody is recovered fromculture by conventional methods such as precipitation, ion exchangechromatography, affinity chromatography, or the like. The antibodiesdescribed herein are also recovered from hybridoma cell cultures byconventional methods for purification of IgG or IgM as the case may bethat heretofore have been used to purify immunoglobulins from pooledplasma, e.g., ethanol or polyethylene glycol precipitation procedures.The purified antibodies are sterile filtered, and optionally areconjugated to a detectable marker such as an enzyme or spin label foruse in diagnostic assays of test samples.

The antibodies of this invention are obtained from any animal species,but ordinarily are from murine or rat. Once a monoclonal antibody havingthe desired specificity and affinity is obtained, other conventionalmodifications of the antibodies are within the scope of this invention.For example, the complementarity determining regions of an animalantibody, together with as much of the framework domain as is needed,are substituted into an antibody of another animal species or class toproduce a cross-class or cross-species chimeric antibody. Fragments orother amino acid sequence variants of monoclonal antibodies also areencompassed within the meaning of antibody as that term is used herein,for example, Fab, Fab' or (Fab')2 fragments, single chain antibodies, bior poly specific antibodies, and the like.

The antibodies of this invention are from any suitable class or isotype,e.g. IgG, IgM, IgA, IgD or IgE. They may or may not participate incomplement binding or ADCC.

Typically, hybridomas which are capable of binding to the immunogen arescreened for the ability to bind to the hapten itself in typical testsamples (plasma, serum and the like) with the requisite degree ofaffinity. The desired affinity will depend upon the use intended for theantibody, but should be adequate to function in a conventionalcompetitive-type ELISA or radioimmunoassays, or in conventional EMITimmunoassays.

The antibodies of this invention are used in such assays together with alabeled form of the compounds of the invention. Alternatively, theantibody is labeled. Suitable labels are well-known and includeradioisotopes, enzymes, stable free radicals, fluorophors,chemiluminescent moieties and other detectable groups heretoforeemployed to prepare covalent conjugates for use in assays. Methods forlinking the labels to ligand amino groups, or amino acid side chains ortermini of polypeptides, are known and are suitable for use herein.Other suitable linking methods will be apparent to the ordinary artisan.Labels are conveniently bound to the thiepanes herein at the same sitesused for bonding to antigenic polypeptides.

The antibodies and labeled ligands herein optionally are assembled intokits for use in therapeutic drug monitoring or evaluation, or forprocess quality control, and used in the conventional manner.

The invention also relates to methods of detecting HIV protease in asample suspected of containing HIV protease comprising the steps of:treating a sample suspected of containing HIV protease with acomposition comprising a compound of the invention bound to a label; andobserving the effect of the sample on the activity of the label.

Compositions of the invention are inhibitors of HIV protease. As suchfrequently the compositions will bind to locations on the surface or ina cavity of HIV protease having a geometry unique to HIV protease.Compositions binding HIV protease may bind with varying degrees ofreversibility. Those compounds binding substantially irreversibly areideal candidates for use in this method of the invention. Once labeled,the substantially irreversibly binding compositions become probes forthe detection of HIV protease.

Uses of the Compounds of the Invention.

Compositions of the invention are screened for inhibitory activityagainst HIV protease by any of the conventional techniques forevaluating enzyme activity. Within the context of the invention,typically compositions are first screened for inhibition of HIV proteasein vitro and compositions showing inhibitory activity are then screenedfor activity in vivo. Compositions having in vitro Ki (inhibitoryconstants) of less then about 5×10⁶ M, typically less than about 5×10⁷ Mand more typically less than about 5×10⁸ M are excellent candidates forin vivo screening.

Useful in vitro screens have been described in detail and will not beelaborated here. However, the above cited work of Billich, A.; Billich,S.; and Rosenwirth, B; Antiviral Chem. & Chemoth., 1991, 2(2), 65-73,discloses suitable assays for HIV protease.

Useful in vivo screens have also been described. The above cited work ofWong, Y.; Burcham, D.; Saxton, P.; Erickson-Viitanen, S.; Grubb, M.;Quon, C.; and Huang, S.-M.; Biopharm. & Drug Disp., 1994, 15, 535-544,discloses suitable pharmacokinetic evaluation of HIV protease inhibitorsin rats and dogs.

Another typical assay is described below in the Examples section of thisspecification.

The compositions of the invention bind HIV protease. Accordingly, theyare useful in any of the assay methods described. They are alsoinhibitors of HIV protease, and as a result are useful as negativecontrols and analytical standards in any of the described methods ofassay for HIV protease activity. These uses are distinct in that acomposition of the invention which binds HIV protease, whether in aninhibitory manner or not, is useful for immobilizing HIV protease in anyheterogeneous assay system. A composition which inhibits HIV protease isuseful for suppressing HIV protease in an assay which detects HIVprotease activity, thereby acting as a negative control or analyticalstandard.

Another aspect of the invention relates to methods of inhibiting theactivity of HIV protease comprising the step of treating a samplesuspected of containing HIV protease with a composition of theinvention.

Within the context of the invention samples suspected of containing HIVprotease include natural or man-made materials such as living organisms;tissue or cell cultures; biological samples such as biological materialsamples (blood, serum, urine, cerebrospinal fluid, tears, sputum,saliva, tissue samples, and the like); laboratory samples; food, water,or air samples; bioproduct samples such as extracts of cells; and thelike. Typically the sample will be suspected of containing an organismwhich produces HIV protease, frequently a pathogenic organism such as avirus, most typically, HIV. Samples can be contained in any mediumincluding water and organic solvent/water mixtures. Typically, samplesinclude living organisms such as mammals and man made materials such asbioproduct samples, more typically, samples include humans.

The treating step of the invention can involve adding the composition ofthe invention to the sample or it can involve adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of HIV protease after application of thecomposition can be observed by any method including direct and indirectmethods of detecting HIV protease activity. Quantitative, qualitative,and semiquantitative methods of determining HIV protease activity areall contemplated. Typically one of the screening methods described aboveare applied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

The compounds of the invention are polyfunctional. As such theyrepresent a unique class of monomers for the synthesis of polymers. Byway of example and not limitation, the polymers could include polyamidesand polyesters. Polyamides and polyesters are materials of well knownutility and the present monomers provide access to polymers havingunique pendent functionalities.

Polymers are prepared from the compounds of the invention byconventional techniques. Polyesters are prepared from the compoundshaving a carboxylic acid group and an alcohol or other leaving group.Alternatively, a diol composition of the invention is reacted with adiacid monomer. Polyamides are prepared from the compounds of theinvention containing one or more amine groups.

The compounds of the invention are also a unique class of polyfunctionalsurfactants. The sulfur group Qa and the groups comprising E, G, T, andU having a chain of carbon atoms are spatially separated by the7-membered ring structure and thus have the properties of bi-functionalsurfactants. As such they have useful surfactant, surface coating,emulsion modifying, rheology modifying and surface wetting properties.

As polyfunctional compounds with defined geometry and simultaneouslycarrying polar and non-polar moieties, the compounds of the inventionare useful as a unique class of phase transfer agents. By way of exampleand not limitation, the compounds of the invention are useful in phasetransfer catalysis and liquid/liquid ion extraction (LIX).

The compounds of the invention optionally contain asymmetric carbonatoms in groups E, G, T, or U. As such, they are a unique class ofchiral auxiliaries for use in the synthesis or resolution of otheroptically active materials. For example, a racemic mixture of carboxylicacids can be resolved into its component enantiomers by: 1) forming amixture of diastereomeric esters with a compound of the invention havingone or more --OH groups; 2) separating the diastereomers; and 3)hydrolyzing the ester structure. Racemic acids are also separated byamide formation with an amine function of the molecule of the invention.Further, such a method can be used to resolve the compounds of theinvention themselves if optically active acids, bases or alcohols areused instead of racemic starting materials.

Exemplary Methods of Making the Compositions of the Invention General

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated in"Compendium of Organic Synthetic Methods" (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "AdvancedOrganic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985);as well as "Comprehensive Organic Synthesis. Selectivity, Strategy &Efficiency in Modern Organic Chemistry. In 9 Volumes.", Barry M. Trost,Editor-in-Chief (Pergamon Press, New York, 1993 printing). Many knowntechniques for manipulating the sulfur atom of the compositions of theinvention are described in Reid, E. Emmet; "Organic Chemistry ofBivalent Sulfur", vol. 1, 1958, vol. 2, 1960, vol.3, 1960, vol. 4, 1962,vol. 5, 1963, and vol. 6, 1965 (Chemical Publishing Company, New York).

A number of exemplary methods for the preparation of the compositions ofthe invention are provided below. These methods are intended toillustrate the nature of such preparations and are not intended to limitthe scope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, workup procedures, and the like, will be those common in theart for the particular reaction to be performed. The incorporatedreference material, together with material cited therein, containsdetailed descriptions of such conditions. Typically the temperatureswill be -100° C. to 200° C., solvents will be aprotic or protic, andreaction times will be 10 seconds to 10 days. Workup typically consistsof quenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.) or at temperaturescorresponding to the boiling point of solvents used in the reaction,although for metal hydride reductions frequently the temperature isreduced to 0° C. to -100° C. Solvents are typically protic for sodiumborohydride reductions and may be either protic or aprotic foroxidations. More typically, oxidations of hydroxy groups pendant on thethiepane ring to form corresponding carbonyls are carried out inrefluxing toluene. Reaction times are adjusted to achieve desiredconversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to -100° C.) are also common.More typically, Claisen-Schmidt condensations are carried out inrefluxing toluene. Solvents can be either protic (common inequilibrating reactions) or aprotic (common in kinetically controlledreactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g. inert gasenvironments) are common in the art and will be applied when applicable.

In the schemes P indicates a hydrolytic ally cleavable protecting group.Such groups have been described in the above cited work of Greene.Ordinarily such groups include silyl ethers, esters, amides and thelike.

Scheme 1

The starting thiepane diols for these preparations are available fromD-mannitol and D-sorbitol by literature methods. U. Kuszmann and P.Sohar. Carb Res. 56, 105-115 (1977) for D-manno and L-idito and J.Kuszmann and P. Sohar. Carb Res. 48, 23-32 (1976) for D-sorbito.) Theenantiomeric series (illustrated as diols 1) is available in analogousfashion from L-mannonolactone and L-glucuronolactone after sodiumborohydride reduction by the method of H. L. Frush, H. S. Isbell, J. Am.Chem. Soc. 78, 2844-2846 (1956).

Combined Oppenhauer oxidation, C. Djerassi Org. Reactions, 6, 207 (1951)and Claisen-Schmidt condensation, House p 633, Modern SyntheticReactions 2nd ed., W. A. Benjamin, Menlo Park Ca (1972); G. A. Hill andG. M. Bramann, Org. Syn. Coll Vol 1, 81 (1944); C. S. Marvel and W. B.King Org. Syn. Coll Vol 1, 252 (1944) provide the α-β unsaturatedketones 2.

Simultaneous conjugate reduction and ketone reduction by methods such asthose described in N. Greeves "Reductions of C═O to CHOH by MetalHydrides" p 1-78 in Vol. 6 sect 1.1 of Comprehensive Organic Synthesis,Trost and Fleming Ed. Pergamon Press (1991) provides the saturatedalcohols 3. In particular, nickel based conjugate reduction, L.Mordenti, J. J. Brunet and P. Caubere, JOC, 44, 2203 (1979); J. J.Brunet, L. Mordenti and P. Caubere, JOC, 43, 4804 (1979); and P.Caubere, Ang. Chem. Int. Ed. Engl. 22, 599 (1983) minimizes the amountof allylic alcohol obtained in the reduction.

Repeating this two step sequence appends the second carbon boundsubstituent in a less stereoselective fashion from which thediastereomeric thiepane diols 5, 6 and 7 are obtained, readily separableby chromatography.

Scheme 2

Diols 5, 6 or 7 are individually alkylated by methods such as theWilliamson ether synthesis described in March Advanced Organic ChemistryOrg. 2nd, reaction 0-14 p 357 and Feuer and Hooz, pp446-450, 460-468 inThe Chemistry of the Ether Linkage, S. Patai Ed., Interscience Pub., NewYork, N.Y. (1967) or arylated C. Paradisi "Arene Substitution viaNucleophilic Addition to Electron Deficient Arenes" p423-450 inComprehensive Organic Synthesis V4 sect 2.1, Trost and Fleming Ed.,Pergamon Press, (1991); J. B. Hynes, J. Heterocyclic Chem. 25, 1173-1177(1988); or reductively alkylated such as is described by S. Hatakeyama,H. Mori, K. Kitano, H. Yamada and M. Nishizawa, Tet. Lett. 35, 4367-4370(1994) to provide mono- or diethers 8. Monoethers may be etherified withthe different groups to provide unsymetrically substituted diethers 8.

Diols 5-7 may also be acylated with a variety of methods to form estersor carbamates 8.

Removal of the acetonide group under standard conditions, L. F. Wiggins,J. Chem. Soc. 13 (1946) gives the thiepane diol 9.

Oxidation, B. M. Trost, D. P. Curran, Tet. Lett. 22, 1287 (1981); K. S.Webb., Tet. Lett. 35, 3457-3460 (1994) gives the corresponding sulfoxide10 or sulfone 11 analogs depending on the reaction stoichiometry.

Alternatively the acetonide may be retained to the end and removed aftersulfur oxidation. This sequence is advantageous for those stereochemicalrelationships (idito) which favor sulfur participation and resultingring contraction, J. Kuszmann and P. Sohar., Carb Res. 56, 105-115(1977).

The diols 9 are converted to the corresponding epoxides 11 by methodssuch as those described in O. Mitsunobu "Synthesis of Alcohols andEthers" p25-31 in Vol. 1 sect 1.1.3.2 of Comprehensive OrganicSynthesis, Trost and Fleming Ed., Pergamon Press (1991); D. R. Hicks andB. Fraser-Reid, Synthesis 203 (1974); and 0. Mitsunobu et al. Chem.Lett. 1613 (1980)).

The corresponding epoxy sulfoxides 12 and sulfones 13 are obtained byoxidation as described above.

Scheme 3

Alternatively, the thiepane diols 1 are oxidized by Dess-Martin reagentR. E. Ireland and L. Liu, J. Org. Chem. 58, 2899 (1993); D. B. Dess andJ. C. Martin, J. Am. Chem. Soc. 113, 7277 (1991) to the symmetricaldiketone 14 which is converted to its bis lithium or silyl enolate, E.J. Corey and A. W. Gross, Tet. Lett. 25, 495 (1984) and T. H. Chan "EnolEthers" p 595-628 in Vol. 2 sect 2.3 of Comprehensive Organic Synthesis,Trost and Fleming Ed., Pergamon Press (1991) and then mono orbis-alkylated by methods such as those discussed in Drury Caine"Alkylation of Enolates" p 1-63 in Vol. 3 sect 1.1 of ComprehensiveOrganic Synthesis, Trost and Fleming Ed., Pergamon Press (1991) to givethe diketone 15. 15 is also obtained by Dess-Martin oxidation of theunsymmetrical diol 7. Reduction with sodium borohydride in methanolstereoselectively provides the symmetrical diol 5.

Scheme 4

The initial thiepane diols 1 may also be oxidized to the diastereotopicsulfones 16, 17 or 18 by methods described earlier. Generation of thesulfone polyanion and carbon alkylation, A. Krief "Alkylation of Sulfurand Selenium Containing Carbanions" p 85-191 in Vol. 3 sect 1.3 ofComprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press(1991); V. Cere, Tet. Lett. 5239 (1978); R. Tanikaga et al., Tet. Lett.28, 3705 (1987); T. Sato et al., Tet. Lett. 28, 5677 (1987) provides thediastereomeric relationships 19, 20 and 21. Subsequent O-alkylation,arylation or acylation and acetonide removal as discussed for Scheme 2provide the sulfone diols 22, 23 or 24. Alternatively, the thiepanediols 1 can be O-alkylated, converted to the sulfones and thenC-alkylated to provide the same isomers, H. Altenbach, pp 359-372 inAntibiotics and Antiviral Compounds, K. Krohn, H. A. Kirst and H. MaagEd., VCH Publishers, Inc., New York, N.Y. (1993). The choice of reactionsequences depends on the physical and mechanical properties of theintermediates.

Scheme 5

The epoxy derivatives 25 are converted to azido alcohols 26 or 27 oramino alcohols 28 or 29 by methods such as those discussed in O.Mitsunobu "Synthesis of Amines and Ammonium Salts" p65-101 in Vol. 6sect 1.3 of Comprehensive Organic Synthesis, Trost and Fleming Ed.,Pergamon Press (1991).

The epoxides are also reduced by methods such as those discussed in S.Murai "Reduction of Epoxides" p871-893 in Vol. 8 sect 4.4 ofComprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press(1991) and Y. Fort et al. Tet. Lett. 26, 3111 (1985) to provide themonoalcohol analogs 30 and 31.

Azido alcohols 26 or 27 after adjustment of the sulfur oxidation stateare reduced to the corresponding amino alcohols 28 or 29 by methods suchas those listed in R. C. Larock, p 409-410 in Comprehensive OrganicTransformations, VCH Publishers, New York, N.Y. (1989).

Scheme 6

The acetonide of dimethyl L-tartrate 32 is converted into the diketone33 by the method of I. Kikkawa and T. Yorifuji, Synthesis 877-880(1980). The bis-silyl enol ether 34 is prepared by the methods of H.Emde et al., Liebigs Ann. Chem. 1643 (1981); S. Torkelson and C.Ainsworth, Synthesis 431 (1977); or other methods as discussed in T. H.Chan "Enol Ethers" p 595-628 in Vol. 2 sect 2.3 of Comprehensive OrganicSynthesis, Trost and Fleming Ed., Pergamon Press (1991).

The bis-enol ether 34 is cyclized via SCl2 according to the method of M.Muehlstaedt, D. Martinez and P. Schneider, J. Prakt. Chemie. 315,940-948 (1973) to diketone 15 which is reduced to diol 5 as discussedbefore.

Alternatively 34 is halogenated by methods such as J. Org. Chem. 39,1785 (1974), J. Org. Chem. 52, 3346 (1987) and Synthesis 194 (1976) tothe bis haloketone and cyclized with sulfide reagents such as NaHS orNa2S to give the cyclic diketone 15.

Scheme 7

The lactol 35 obtained from an inositol derivative according to Fujami,Tet. Lett. 4771 (1967) is converted by the method of I. Kikkawa and T.Yorifuji, Synthesis 877-880 (1980) to the keto alcohol 36.Stereoselective reduction by methods such as T. Nakata et al., Tet.Lett. 24, 2653 (1983) or others as discussed in N. Greeves "Reductionsof C═O to CHOH by Metal Hydrides" p 1-78 in Vol. 6 sect 1.1 ofComprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press(1991) provides the diol 37. Activation with tosylate and displacementby sulfide provides the thiepane bisacetonide 38. Partial deprotectionand equilibration of the acetonide in analogy to J. Kuszmann, P. Sohar,C. Horvath, Carb. Res. 50, 45-52 (1976) provides the thiepane diol 39which is manipulated in accord with Schemes 2 and 5.

Scheme 8

Diol 7 obtained as described in Scheme 1 is monoalkylated to ether 40,either directly or via a monoprotected intermediate. After oxidation tothe sulfone 41, the equatorial alcohol is eliminated viamethanesulfonylchloride and triethyl amine in methylene chloride tovinyl sulfone 42. Michael addition of various nucleophiles such asamines, thiols or carbon based nucleophiles such as cuprates providesstructures such as 43 or its stereoisomers. Deprotection provides thediol sulfones 44. The preparation and reactions of vinyl sulfones arereviewed in Simpkins, N. S. "Sulphones in Organic Synthesis", PergamonPress, Oxford (1993).

Scheme 9

Diol 5 is activated by acylation or alkylation to 45 followed byoxidation to the corresponding sulfone 46. Base induced eliminationprovides the divinyl sulfone 47. Other diol stereoisomers may beoxidized to the sulfone first and then dehydrated to the desired sulfone47. Nucleophilic addition with amines, or thiols gives 48, or 50. Alkoxynucleophiles will provide O-linked structures such as 64 (Scheme 12).With some nucleophiles, the elimination and Michael addition may occurin the same pot to provide the adducts directly from 46. Acetonideremoval provides the sulfone diol 49, or 51.

Scheme 10

An alternative route to the divinyl sulfone 47 involves condensation ofsulfone 54 with L-tartaric ester-derived dialdehyde 55 followed bydehydration.

Scheme 11

Tosyl acetate 56, derived from L-mannitol as described in Example 1 isconverted to the thioether 57. Alkylation or arylation of the freehydroxyls to 58 followed by sulfur oxidation to diastereomericsulfoxides 59 and Pummerer rearrangement gives 60 as a protected versionof the dialdehyde 61. Nucleophilic addition to the aldehyde functionprovides the diol 62. Stereoselectivity in this addition can becontrolled by the adjacent chiral centers and by the use of variousadditives such as Lewis acids or cosolvents to enhance or diminishinherent directing affects. Alternatively, diastereomers of diol 62 canbe oxidized to the corresponding diketone and reduced to the desiredstereochemistry. After activation of the hydroxyls to structures 63,ring closure to structures 8 will occur. Oxidation to sulfones 64 anddeprotection provides the sulfone diols 11.

Scheme 12

The order of sulfur oxidation and acetonide removal can be altered atwill as illustrated. Diastereomers of 8 with equatorial oxysubstituentsmay undergo ring contraction under acid catalysed deprotection at thesulfide oxidation state. Such rearrangements are minimized from thesulfoxide 65 or sulfone 64 oxidation states.

Scheme 13

The dialdehyde 61 is a versatile intermediate which can be olefinated tothe diene 65 or epoxidized to 66, directly or via 65. Thiepane ringformation can occur to provide diol 67 (R═H). Regioselectivity of theepoxide opening and ring closure reactions can be moderated by thesteric and electronic characteristics of the R" substituent as well asby solvent and counter ion effects. Thiepane 67 can be converted to diolsulfones in a variety of routes, retaining the extra alkoxy substituentsor eliminating them to olefin or saturated side chains as illustrated instructures 8 or 68. Divinyl sulfone 68 can be further elaborated byconjugate addition reactions similar to those described in Scheme 8 orby conjugate reduction to provide saturated structures such as 64(Scheme 11).

Scheme 14

The tartrate derived silyl enol ether may be condensed with thionylchloride to give the diketosulfoxide 70 which can be reduced to thiepanediol 5 or oxidized to the sulfone 71 and then reduced and eliminated togive the divinyl sulfone 47. The reaction of silyl enolethers withthionyl chloride is described in B. Zwanenburg, "Phosphorus, Sulfur andSilica" 43, 1-24 (1989).

Scheme 15

Chiral 102 is readily available by routes described in C. R. Johnson, P.A. Ple, L. Su, M. J. Heeg, J. P. Adam., Synlett 338 (1992) and L.Dumortier, P. Liu, S. Dobbelarere, J. Van der Eycken, M. Vanderwalle.,Synlett, 243 (1992). Another preparation of 104 is described by H-JAltenbach in Antibiotics and Antiviral Compounds, Chemical Synthesis andModification, Eds.; K. Krohn, H. A. Kirst, H. Maag: VCH PublishningInc., p. 359 (1993). Saponification of acetate 104 followed byalkylation with benzylbromide in the presence of sodium hydride in THFprovides 105 which is subjected to ozonolysis to produce 106. Chelationcontrolled addition of benzyl Grignard reagent to aldehyde 106 leads to107. Mesylation of 107 and hydrogenolysis of benzyl groups followed bytreatment of the hydroxy mesylate with DBU generates epoxide 108.Formation of the seven membered ring sulfide 109 is accomplished byepoxide opening with Na2S.

Scheme 16

The mixture of ketoalcohols (Table 101, compounds 31 and 32) arecondensed with alkyl amines under conditions of reductive amination toprovide the amino alcohols 201. Etherification of the hydroxy functionfollowed by oxidation with Oxone in methanol without buffering, providesthe sulfone 203. Deprotection gives the aminodiol sulfone 204.

Schemes 17

Treatment of vinyl sulfone 42 with benzyl amine in refluxing ethanolaffords the amino sulfone 205. Deprotection in 95% TFA/water at 85° for2 hrs affords the diol 206.

Scheme 18

Alternatively 42 is deprotected in 50% TFA/30% methanol/20% water for 30minutes to provide the vinyl sulfone diol 207. Treatment of 207 withvarious primary amines in refluxing solvents such as ethanol or tolueneprovides the aminosulfones 208.

Scheme 19

Monoalcohols 209 or 41 are oxidized to the keto sulfones 210. Enamineformation to the vinylogous sulfonamides 211 will occur underdehydrating conditions such as azeotropic removal of water, or treatmentwith drying agents such as molecular sieves or magnesium sulfate.Reduction of the enamine provides the aminosulfones 212.

Scheme 20

The bis-nitrone 215 derived from the corresponding known tartaricdialdehyde derivative, A. Krief, et al., Tetrahedron, 45, 3039-3052(1989) by methods such as those described in A. Dondoni, Syn. Comm. 24,2537-2550 (1994) is condensed with divinyl sulfones 216, prepared fromaldehydes according to H. J. Backer, Recueil, 72, 119 (1953), to affordthe bisisoxazolidines 217 in analogy to P. Deshong et al., JACS 106,5598 (1984). Reductive cleavage of the N--O bond affords the diol 218which is dehydrated to the exocyclic divinylsulfone 219. Michaeladdition of N, S, O or C based nucleophiles provides the aminosulfones220. Alternatively, when R" is not hydrogen, hydrogenolysis ordehydration/reduction may afford the corresponding amionosulfones 220.Deprotection provides the aminodiols 221.

Scheme 21

Alternatively the bisisoxazolidines 217 can be built sequentially by thecondensation of known nitrones 222, S. Saito et al., Synlett, 282-284(1994) with divinylsulfones 216 to provide the monocyclic isoxazolidine223. Deprotection of the protected primary alcohol function is followedby oxidation to the aldehyde 224. Condensation with an N-substitutedhydroxylamine provides the nitrone 225 which can then undergo anintramolecular cycloaddition reaction to 217 optionally deprotected tosulfone diol 226.

Scheme 25

The starting tartrate esters 251 are available from natural L-tartaricacid by literature methods, L. T. Rossaano, Tet. Lett., 36, 4967 (1995).

Treatment with N,O-dimethylhydroxylamine, S. Nahm, Tet. Lett., 39, 3815(1981) provide the bis-amides 252 which can be used to acylate metalatedsulfides, sulfoxides or sulfones 253, to afford keto amides 254 afteracid hydrolysis. Subsequent α-thio metalation and intramolecularacylation provide diketones 255. Additionally, diketones 255 may beavailable directly from bis-amides 252 via acylation of thio1,3-dianions, E. M. Kaiser, Tet. Lett., 3341 (1967); S. Patai, Ed., "TheSyntheses of Sulphones, Sulphoxides and Cyclic Sulphides", J. Wiley &Sons, New York, N.Y. (1994).

Reduction with sodium borohydride in methanol stereoselectively providesthe symmetric diols 256.

O-alkylation, arylation or acylation (as discussed herein) followed bysulfer oxidation, B. M. Trost, Tet. Lett. 22, 1287 (1981) afford thecorresponding sulfone analogs 257.

Scheme 26

Keto amides 254 are also available in sequential fashion starting fromdiols 258, S. Terashima, Tet. Lett. 23, 4107 (1982) and L. J. Rubin, J.Am. Chem. Soc. 74, 425 (1952).

Mono protection followed by oxidation and esterification provide esters259 which are converted to the corresponding N-methoxy-N-methyl amides260 as described in Scheme 25. Acylation of sulfer reagents 253 thenprovide ketones 261.

Deprotection of the remaining primary alcohol provides an appropriatesubstrate on which to repeat the oxidation, esterification and amideformation sequence, which provide the keto amides 254.

Scheme 27

Tartrate esters 251 are reduced to dialdehydes 262 with DIBAL, A. Krief,Tetrahedron, 45, 3039 (1989).

Alkylation of metalated sulfer reagents 253 provide alcohols 263 ordiols 264 directly if 1,3-dianions are utilized (as discussed in Scheme25).

Oxidation of diols 264 by the Dess-Martin periodinane reagent, D. B.Dess, J. Am. Chem. Soc. 113, 7277 (1991) provide diones 255.

Scheme 28

Mono protection and oxidation of diols 258 provide aldehydes 265 (H.Iida, J. Org. Chem., 52, 3337 (1987) and T. Mukaiyama, Tetrahedron, 46,265 (1990). Treatment of aldehydes 265 with metalated sulfer reagents253 allow access to the mono protected diols 266. Protecting groupremoval followed by oxidation provide aldehyde intermediates 263.

Scheme 29

Acylation, B. M. Trost, Ed., Comp. Org. Synth. Vol 2, Pergamon Press,Tarrytown, N.Y. (1991) of the bis-enol ethers derived from sulferreagents 267, M. T. Reetz, Org. Syn. Coll. Vol. VII, 424 (1990) affordthe bis-1, 3-diketones 269.

Conjugate reduction, C. M. Belisle, Tet. Lett. 35, 5595 (1994) and E.Yoshii, Chem. Pharm. Bull. 25, 1468 (1977) provides diols 270.O-alkylation, arylation or acylation and sulfer oxidation (describedherein) provide sulfones 271.

Scheme 30

Acylation of the mono enol ether derived from sulfer reagents 267 withN-methoxy-N-methyl amides 260 (Scheme 26) as described in Scheme 29,provide the 1,3-diketones 272.

Alcohol deprotection and conversion to the correspondingN-methoxy-N-methyl amides as described in Scheme 26 allow access to ketointermediates 269.

Scheme 31

Wittig olefination of dialdehydes 262, A. Krief, Tetrahedron, 45, 3039(1989) stereo selectively provide (Z,Z)-1,5-dienes 273.

Directed epoxidation, J. Rokash, Tet. Lett. 22, 979 (1981) afforddi-epoxides 274 which provide thiepanes 256 upon treatment with Na₂ S.Alternatively, epoxide opening can be performed sequentially via basichydrolysis of intermediates 275.

Scheme 32

A stepwise route toward intermediate 279 also allow access to thiepane256.

Wittig olefination of aldehydes 265 provide (Z)-olefins 276. Directedepoxidation followed by nucleophilic opening affords alcohols 278.

O-alkylation, arylation or acylation of the secondary alcohol anddeprotection/oxidation of the primary alcohol give aldehydes 279 whichcan be converted to oxiranes 275 by repeating the initial two stepsequence described in Scheme 31.

Scheme 33

Horner-Emmons olefination with (2,2,2-trifluoroethoxy)phosphonatesselectively afford the symmetrical α,β-unsaturated esters 280, D.Boschelli, Tet. Lett., 26, 5239 (1985) and H. Kotsuki, J. Org. Chem.,54, 5153 (1989).

Lithium aluminum hydride reduction, G. R. Newkome, J. Org. Chem., 52,5480 (1987) give allylic alcohols 281 which undergo Sharpless asymmetricepoxidation, T. Katsuki, J. Org. Chem., 47, 1373 (1982) to provide 282.

Hydroxyl protection followed by epoxide opening as described in Schemes31 and 32 afford thiepanes 285.

O-alkylation, arylation or acylation provide the bis-hydroxymethylthiepanes 286.

Interconversion of the free hydroxyls to suitable leaving groups (e.g.mesylates, tosylates, halides, etc.), nucleophilic displacement andsulfide oxidation afford sulfones 257.

Scheme 34

Epoxides 284 can also be assembled in stepwise fashion following thegeneral protocol described in Scheme 32.

Horner-Emmons reaction of aldehydes 265 with(2,2,2-trifluoroethoxy)phosphonates provide (Z)-olefins 287.

Ester reduction followed by Sharpless asymmetric epoxidation affordoxiranes 288. Nucleophilic ring opening and primary alcohol protectiongive intermediates 289 which can be homologated to epoxides 284 asdescribed in Scheme 32.

Scheme 35

An optional method to stereo selectively prepare bis-(Z)-olefins 273involve a formyl to ethynyl conversion as described by E. J. Corey, Tet.Lett. 3769 (1972). Treatment of dialdehydes 262 with CBr₄ and PPh₃afford intermediate bis-vinylidene dibromides which undergo eliminationand metal halogen exchange upon treatment with alkyllithium bases. Theresultant terminal alkynes can be isolated, remetalated, and homologatedto provide bis-alkynes 290 or obtained directly by alkylation of theintermediate alkynyllithium.

Partial reduction of 290 utilizing the Lindlar protocol, H. Lindlar,Org. Syn. Coll. Vol. V, 880 (1973) provide bis-(Z)-olefins 273 which canbe further manipulated as described in Scheme 31.

Scheme 36

An alternative method to stereo selectively prepare (Z)-olefins 276involve a formyl to ethynyl conversion as described by E. J. Corey, Tet.Lett. 3769 (1972). Treatment of aldehydes 265 (described herein) withCBr₄ and PPh₃ afford intermediate vinylidene dibromides which undergoelimination and metal halogen exchange upon treatment with alkyllithiumbases. The resultant terminal alkynes can be isolated, remetalated, andhomologated to provide alkynes 291 or obtained directly by alkylation ofthe intermediate alkynyllithium.

Partial reduction of 291 utilizing the Lindlar protocol, H. Lindlar,Org. Syn. Coll. Vol. V, 880 (1973) provide (Z)-olefins 276 which can befurther manipulated as described in Scheme 32.

Scheme 37

Conversion of diols 258 to bis-halomethyl compounds 292 can beaccomplished by treatment with PPh₃ and CX₄, M. Falorni, J. Org. Chem.51, 5291 (1986). Treatment of 292 with PPh₃ provide the Wittig salts293.

Access to olefins 273 (Scheme 31) is possible by Wittig reaction between293 and suitable aldehydes.

Scheme 38

Utilizing mono protected diol 294 (described herein), Wittig salt 296can be prepared according to the procedure described in Scheme 37.

Olefination of 296 provide 276 which is elaborated to compounds 278according to

Scheme 32. O-alkylation, arylation or acylation of the secondaryalcohol, followed by deprotection of the primary alcohol affordcompounds which can be subjected to the above sequence (halogenation,Wittig olefination) allowing entry to compounds 275.

Scheme 50

Alkylation of dianion of 54 with allyl bromide affords diene 310.Formation of the seven membered ring compound 311 is accomplished byring-closing-metathesis (RCM) of 310 by methods described by Grubbs andcoworkers, J. Am. Chem. Soc., 114, 7324 (1992). Oxidation of 311 leadsto diketone 312, Comprehensive Organic Transformations, Ed. R. C.Larock: VCH Publishers, Inc., pp. 593-594 (1989) and references citetherein which can be reduced to diol 313 (R₁, R₂ ═OH). Reductiveamination of 312 leads to Diamine 313 (R₁, R₂ ═NHR₅). In the sequence ofreduction and reductive amination affords amino alcohol 313 (R₁ ═NHR₅,R₂ ═OH). Di hydroxylation of 313 affords cis-diol 314 (R₃ =R₄ =OH).Epoxidation of 313 followed by opening of epoxide gives trans-diol.Hydroboration of 313 provides mono-alcohol 314 (R₃ ═H, R₄ ═OH). R groupsdepicted in Scheme 50, in particular those of compound 314, are selectedto be consistent with the disclosure of the compositions herein.Separation of isomers of compound 314 are performed by conventionalmethods.

Scheme 51

Condensation of α,β-unsaturated aldehyde and dianion of 54 affordscorresponding diene alcohol 315 which is protected to form ether 316.Formation of the seven membered ring compound 317 is accomplished byring-closing-metathesis (RCM) of 316 by methods described by Grubbs andcoworkers, J. Am. Chem. Soc., 114, 7324 (1992). Di hydroxylation of 317affords cis-diol 318 (R₃ ═R₄ ═OH). Epoxidation of 317 followed byopening of epoxide gives the trans-diol. Hydroboration of 317 providesmono-alcohol 318 (R₃ ═H, R₄ ═OH). R groups depicted in Scheme 51, inparticular those of compound 318, are selected to be consistent with thedisclosure of the compositions herein. Separation of isomers of compound318 are performed by conventional methods.

In each of the above exemplary schemes it may be advantageous toseparate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps areseparated and/or purified (hereinafter separated) to the desired degreeof homogeneity by techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example, size exclusion or ion exchange chromatography,high, medium, or low pressure liquid chromatography, small scale andpreparative thin or thick layer chromatography, as well as techniques ofsmall scale thin layer and flash chromatography.

Another class of separation methods involve treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Each of the cited works above is incorporated by reference in itsentirety. Specifically cited sections or pages of the above cited worksare incorporated by reference with specificity at the location of thecitation and for the purpose appropriate for the context of thecitation. The invention has been described in detail sufficient to allowone of ordinary skill in the art to make and use the subject matter ofthe following claims. It is obvious that certain modifications of themethods and compositions of the following claims can be made within thescope and spirit of the invention.

Scheme 60

Chiral aldol condensation of butenoic acid derivatives such as 400 usingany number of chiral auxiliaries Xc such as those developed by Evanswith various aldehydes 401 such as phenylacetaldehyde gives thenon-racemic aldol product 402. Hydrolysis provides the β-hydroxyacid403. Curtius rearrangement provides the cis substituted oxazolidinone404 which may be optionally alkylated on nitrogen to provide 405.Manipulation of the heterocycle by direct attack by sulfide anion oroptionally by hydrolysis of the ring followed by optional protection ofthe nitrogen and activation of the hydroxyl group and displacement withsulfide dianion provides the symmetrical sulfide 406. Optionallyunsymmetrical analogs can be prepared by appropriate manipulation ofthese intermediates. Optional protection of the nitrogens of 407followed by ring closure via olefin metathesis as illustrated by H.Schmalz, Angew. Chem. Int. Ed. Engl, 34, 1833 (1995) provides the cyclicsulfides 407 or 408. The oxidation state of these intermediates may beeither the sulfide, sulfoxide or sulphone.

Scheme 61

Cis dihydroxylation of 408 provides a single diastereomer 409 which maybe deprotected and adjusted to the cis diol diastereomer 413.Cyclization of 409 into the cis protecting group provides theoxazolidinone 410 which allows activation of the remaining hydroxyl anddisplacement via neighboring group participation to the symmetrical 411.Hydrolysis of the carbamate rings provide the trans diols 412. Finaladjustment of sulfur oxidation state may be accomplished at this pointif not earlier.

Scheme 62

Methylenation of dialdehydes 450 (prepared by conventional means) affordbis-olefins 451, J. Am. Chem. Soc., 106, 7514 (1984).

Metal carbene facilitated metathesis, G. C. Fu, J. Am. Chem. Soc., 115,9856 (1993), provide alkenes 452 which undergo cis-dihydroxylation toafford diols 453.

Selective protection of the equitorial hydroxyl followed by oxidation ofthe remaining axial hydroxyl group provide access to ketones 454.Directed reduction from the least hindered face return diols 455following alcohol deprotection.

X is selected from:

--N(R)C(═O)N(R)--;

--C(H)(R)C(═O)C(H)(R)--;

--C(H)(R)SC(H)(R)--;

--C(H)(R)S(═O)C(H)(R)--;

--C(H)(R)S(═O)₂ C(H)(R)--;

--C(H)(R)P(R)C(H)(R)--;

--C(H)(R)P(═O)C(H)(R)--

Other embodiments of X are those found as W on p. 12 of the above citedwork of Lam; et. al. (WO 94/19329).

Scheme 63

Compounds 456 are prepared in a manner consistent with Scheme 1, p. 351of the above cited work of Lam, et. al. (WO 94/19329); Scheme 1 andsupporting disclosure of which are incorporated herein by reference.

Methylenation of dialdehydes 456 afford bis-olefins 457, J. Am. Chem.Soc., 106, 7514 (1984).

Metal carbene facilitated metathesis, G. C. Fu, J. Am. Chem. Soc., 115,9856 (1993), provide alkenes 458 which undergo cis-dihydroxylation toafford diols 459.

Selective protection of the equitorial hydroxyl followed by oxidation ofthe remaining axial hydroxyl group provide access to ketones 460.Directed reduction from the least hindered face return diols 461following alcohol deprotection.

Scheme 64

An alternative preparation of bis-olefins 457 is as follows.Condensation of aldehydes 462 with amines 463 provide imines 464.Nucleophilic addition of a vinyl group (e.g. Vinyl lithium, grignard,cuprate, etc.) afford the allylic amines 465 which are resolved toprovide optically active 466, J. D. Morrison, Ed., Asymmetric Synthesis,Vol 1, Academic Press, Inc., New York, N.Y. (1983). Alternatively,amines 466 may be available directly from imine 464 via stereoselectiveorganometallic addition. Coupling of amines 466 with an appropriateacylating reagent (e.g. CDI, phosgene, etc.) afford bis olefins 457.##STR179##

EXAMPLES Compositions

The compositions described in the Examples are uniquely designated asindicated in Tables 101, 107 and 108 based on the following formula:

                                      TABLE 101                                   __________________________________________________________________________     ##STR180##                                                                   # Z   R1   R2  R3  R4  R5  R6   Z 1 2 3 4 5 6                                 __________________________________________________________________________     1                                                                              S   H    OH  OC(Me).sub.2 O                                                                        OH  H        α                                                                         α                                                                         β                                                                          β                              13                                                                              S   PhCH O   OC(Me).sub.2 O                                                                        OH  H      z   α                                                                         β                                                                          β                              15                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        OH  H      α                                                                         α                                                                         α                                                                         β                                                                          β                              25                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        O   PhCH   α                                                                         α                                                                         α                                                                         β                                                                            z                                 27                                                                              S   Bn   O   OC(Me).sub.2 O                                                                        O   Bn     α                                                                           α                                                                         β                                                                            β                            28                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        OH  Bn     α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                            29                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        OH  Bn     α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          α                           30                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        OH  BN     α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         β                            31                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        O   Bn     α                                                                         α                                                                         α                                                                         β                                                                            β                            32                                                                              S   Bn   OH  OC(Me).sub.2 O                                                                        O   Bn     α                                                                         α                                                                         α                                                                         β                                                                            α                           __________________________________________________________________________

                                      TABLE 107                                   __________________________________________________________________________    # Z    R1 R2   R3  R4  R5   R6                                                                              Z 1 2 3 4 5 6                                   __________________________________________________________________________     1                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OC(Me).sub.2 O--                                                                    --OBn                                                                              H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   2                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   3                                                                              --SO--                                                                             --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              H β                                                                          α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   4                                                                              --SO--                                                                             --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              H α                                                                         α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   5                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   6                                                                              --S--                                                                              --Bn                                                                             --OoCN                                                                             --OC(Me).sub.2 O--                                                                    --OoCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   7                                                                              --S--                                                                              --Bn                                                                             --OoCN                                                                             --OH                                                                              --OH                                                                              --OoCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   8                                                                              --SO--                                                                             --Bn                                                                             --OoCN                                                                             --OH                                                                              --OH                                                                              --OoCN                                                                             H α                                                                         α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                   9                                                                              --SO--                                                                             --Bn                                                                             --OoCN                                                                             --OH                                                                              --OH                                                                              --OoCN                                                                             H β                                                                          α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  10                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OoCN                                                                             --OH                                                                              --OH                                                                              --OoCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  11                                                                              --S--                                                                              --Bn                                                                             --OpCN                                                                             --OC(Me).sub.2 O--                                                                    --OpCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  12                                                                              --S--                                                                              --Bn                                                                             --OpCN                                                                             --OH                                                                              --OH                                                                              --OpCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  13                                                                              --SO--                                                                             --Bn                                                                             --OpCN                                                                             --OH                                                                              --OH                                                                              --OpCN                                                                             H β                                                                          α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  14                                                                              --SO--                                                                             --Bn                                                                             --OpCN                                                                             --OH                                                                              --OH                                                                              --OpCN                                                                             H α                                                                         α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  15                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OpCN                                                                             --OH                                                                              --OH                                                                              --OpCN                                                                             H --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          --                                  __________________________________________________________________________

                                      TABLE 108                                   __________________________________________________________________________    # Z    R1 R2   R3  R4  R5   R6 Z 1 2 3 4 5 6                                  __________________________________________________________________________     1                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OC(Me).sub.2 O--                                                                    --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                              2                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OC(Me).sub.2 O--                                                                    --OH --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                              3                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                              4                                                                              --SO--                                                                             --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                              5                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                              6                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --O--   --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         β                                                                          β                                                                          β                                                                          β                              7                                                                              --SO--                                                                             --Bn                                                                             --OBn                                                                              --O--   --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         β                                                                          β                                                                          β                                                                          β                              8                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OBn                                                                              --O--   --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         β                                                                          β                                                                          β                                                                          β                              9                                                                              --S--                                                                              --Bn                                                                             --O3PM                                                                             --OC(Me).sub.2 O--                                                                    --O3PM                                                                             --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                             10                                                                              --SO--                                                                             --Bn                                                                             --O3PM                                                                             --OC(Me).sub.2 O--                                                                    --O3PM                                                                             --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                             11                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --O3PM                                                                             --OC(Me).sub.2 O--                                                                    --O3PM                                                                             --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                             14                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --O3PM                                                                             --OH                                                                              --OH                                                                              --O3PM                                                                             --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          β                             15                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OC(Me)2O--                                                                          --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          α                            16                                                                              --S--                                                                              --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          α                            17                                                                              --SO--                                                                             --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             β                                                                          α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          α                            18                                                                              --SO.sub.2 --                                                                      --Bn                                                                             --OBn                                                                              --OH                                                                              --OH                                                                              --OBn                                                                              --Bn                                                                             --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          β                                                                          α                            19                                                                              S    Bn OBn  --OC(Me).sub.2 O--                                                                    OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         β                             20                                                                              SO.sub.2                                                                           Bn OBn  --Oc(Me).sub.2 O--                                                                    OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         β                             21                                                                              SO.sub.2                                                                           Bn OBn  --OH                                                                              OH  OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         β                             22                                                                              S    Bn OBn  --OC(Me).sub.2 O--                                                                    OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         α                            23                                                                              SO.sub.2                                                                           Bn OBn  --OC(Me).sub.2 O--                                                                    OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         α                            24                                                                              SO.sub.2                                                                           Bn OBn  --OH                                                                              OH  OBn  Bn --                                                                              α                                                                         α                                                                         α                                                                         β                                                                          α                                                                         α                            25                                                                              S    Bn OBn  --OC(Me).sub.2 O--                                                                    OBn  Bn --                                                                              β                                                                          β                                                                          β                                                                          α                                                                         α                                                                         α                            26                                                                              SO.sub.2                                                                           Bn OBn  --OC(Me).sub.2 O--                                                                    OBn  Bn --                                                                              β                                                                          β                                                                          β                                                                          α                                                                         α                                                                         α                            27                                                                              SO.sub.2                                                                           Bn OBn  --OH                                                                              OH  OBn  Bn --                                                                              β                                                                          β                                                                          β                                                                          α                                                                         α                                                                         α                            __________________________________________________________________________

                  TABLE 120                                                       ______________________________________                                         ##STR181##                                                                   #    Z       R2        R3     R4       R5                                     ______________________________________                                         1   S       OBn       OC(Me).sub.2 O                                                                              OBn                                       2   S       OBn       OH     OH       OBn                                     3   SO      OBn       OH     OH       OBn                                     4   SO.sub.2                                                                              OBn       OH     OH       OBn                                     5   S       O2PM      OC(Me)2O      O2PM                                      6   SO.sub.2                                                                              O2PM      OC(Me)2O      O2PM                                      7   SO.sub.2                                                                              O2PM      OC(Me)2O      O2PMNO                                    8   SO.sub.2                                                                              O2PM      OH     OH       O2PM                                    9   SO.sub.2                                                                              O2PM      OH     OH       O2PMNO                                 10   S       O3PM      OC(Me)2O      O3PM                                     11   SO      O3PM      OC(Me)2O      O3PM                                     12   SO.sub.2                                                                              O3PM      OC(Me)2O      O3PM                                     13   SO.sub.2                                                                              O3PM      OC(Me)2O      O3PMNO                                   14   SO.sub.2                                                                              O3PMNO    OC(Me).sub.2 O                                                                              O3PMNO                                   15   SO.sub.2                                                                              O3PM      OH     OH       O3PM                                   16   SO.sub.2                                                                              O3PM      OH     OH       O3PMNO                                 17   S       O4PM      OC(Me).sub.2 O                                                                              O4PM                                     18   SO.sub.2                                                                              O4PM      OC(Me).sub.2 O                                                                              O4PM                                     19   SO.sub.2                                                                              O4PM      OH     OH       O4PM                                   20   S       O2MT4M    OC(Me).sub.2 O                                                                              O2MT4M                                   21   SO.sub.2                                                                              O2MT4M    OC(Me).sub.2 O                                                                              O2MT4M                                   22   SO.sub.2                                                                              O2MT4M    OH     OH       O2MT4M                                 23   S       OT5M      OC(Me).sub.2 O                                                                              OT5M                                     24   SO.sub.2                                                                              OT5M      OC(Me).sub.2 O                                                                              OT5M                                     25   SO.sub.2                                                                              OT5M      OH     OH       OT5M                                   26   S       O2P       OC(Me).sub.2 O                                                                              O2P                                      27   SO.sub.2                                                                              O2P       OC(Me).sub.2 O                                                                              O2P                                      28   SO.sub.2                                                                              O2P       OH     OH       O2P                                    29   S       OmMe      OC(Me).sub.2 O                                                                              OmMe                                     30   SO.sub.2                                                                              OmMe      OC(Me).sub.2 O                                                                              OmMe                                     31   SO.sub.2                                                                              OmMe      OH     OH       OmMe                                   32   S       OmOMe     OC(Me).sub.2 O                                                                              OmOMe                                    33   SO.sub.2                                                                              OmOMe     OC(Me).sub.2 O                                                                              OmOMe                                    34   SO.sub.2                                                                              OmOMe     OH     OH       OmOMe                                  35   S       OmBr      OC(Me).sub.2 O                                                                              OmBr                                     36   SO.sub.2                                                                              OmBr      OC(Me).sub.2 O                                                                              OmBr                                     37   SO.sub.2                                                                              OmBr      OH     OH       OmBr                                   38   S       OmOBn     OC(Me).sub.2 O                                                                              OmOBn                                    39   SO.sub.2                                                                              OmOBn     OC(Me).sub.2 O                                                                              OmOBn                                    40   SO.sub.2                                                                              OmOBn     OH     OH       OmOBn                                  41   SO.sub.2                                                                              OmOH      OH     OH       OmOH                                   42   S       OmNO.sub.2                                                                              OC(Me).sub.2 O                                                                              OmNO.sub.2                               43   SO.sub.2                                                                              OmNO.sub.2                                                                              OC(Me).sub.2 O                                                                              OmNO.sub.2                               44   SO      OmNO.sub.2                                                                              OH     OH       OmNO.sub.2                             45   SO.sub.2                                                                              OmNO.sub.2                                                                              OH     OH       OmNO.sub.2                             46   SO.sub.2                                                                              OmNH.sub.2                                                                              OH     OH       OmNH.sub.2                             47   SO.sub.2                                                                              OmNH.sub.2 s                                                                            OH     OH       OmNH.sub.2 s                           ______________________________________                                    

                  TABLE 125                                                       ______________________________________                                         ##STR182##                                                                   #    X       R.sub.3   R.sub.4                                                                          R.sub.2                                             ______________________________________                                        1 2 3                                                                              S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR183##                                         4 5 6                                                                              S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR184##                                         7    S       OC(Me).sub.2 O                                                                              ##STR185##                                         8 9 10                                                                             S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR186##                                         11   S       OC(Me).sub.2 O                                                                              ##STR187##                                         12 13 14                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR188##                                         15 16 17                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR189##                                         18   SO.sub.2                                                                              OH  OH                                                                                      ##STR190##                                         19 20 21                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR191##                                         22 23 24                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR192##                                         25 26 27                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR193##                                         28   SO.sub.2                                                                              OH  OH                                                                                      ##STR194##                                         29 30 31                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR195##                                         32   SO.sub.2                                                                              OH  OH                                                                                      ##STR196##                                         33 34 35                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR197##                                         36   S       OC(Me).sub.2 O                                                                              ##STR198##                                         37 38 39                                                                           S SO.sub.2  SO.sub.2                                                                  OC(Me).sub.2 O OC(Me).sub.2 O OH  OH                                                        ##STR199##                                         ______________________________________                                         Bn = benzyl                                                                   mMe = meta xylyl                                                              mOMe = meta methoxybenzyl                                                     mOBn = meta Benzyloxybenzyl                                                   mOH = meta hydroxybenzyl                                                      mBr = meta bromobenzyl                                                        mNO.sub.2 = meta nitrobenzyl                                                  mNH.sub.2 = meta aminobenzyl                                                  mNH.sub.2 s = meta aminobenzyl, methanesulfonate salt                         2P = 2pyridyl-                                                                2PM = 2pyridylmethyl-                                                         2PMNO = 2pyridylmethyl-, Noxide                                               3PM = 3pyridylmethyl-                                                         3PMNO = 3pyridylmethyl-, Noxide                                               4PM = 4pyridylmethyl-                                                         2MT4M = 2methylthiazol-4-ylmethyl-                                            T5M = thiazol5-ylmethyl-                                                 

Abbreviations

Ac=acetyl

Bn=benzyl

Bz=benzoyl

oCN=ortho-cyanophenyl

pCN=para-cyanophenyl

Me=methyl

Ph=phenyl

Ts=toluenesulfonyl

3P=3-pyridylmethyl

Example 1

D-manno thiepane diol acetonide and L-manno thiepane diol acetonideTable 101, compound 1.

D-manno thiepane diol acetonide was prepared from D-mannitol by theprocedure of Kutzman, (Carb. Res. 56, 105-115 (1977)). An improvementuses the 1,6 ditosyl 2,5 diacetyl 3,4 isopropylidene derivative(described in L. F. Wiggins, J. Chem. Soc. 1946, 384-388) in thethiepane forming reaction in place of the diepoxide.

L-manno thiepane diol acetonide (Table 101, compound 1) was prepared inan analogous way. L-mannolactone is the commercial starting material.Reduction by the method of Frush (JACS 78, 2844-2846 (1956)) is combinedwith acetonide formation to provide1,2:3,4:5,6-Triisopropylidene-L-mannitol.

Part 1 1,2:3,4:5,6-Triisopropylidene-L-mannitol A 5-liter 3-necked flaskequipped with solids addition funnel with nitrogen stream, refluxcondensor and thermometer is charged with 178.1 g (1 mol) ofL-mannono-1,4-lactone (Pfahnstiehl) suspended in methanol (2.7 liter)with vigorous stirring. Sodium borohydride (81.2 g, 2 mol) is addedcautiously as a solid so that gas evolution is maintained at a safe rate(45 min). A nitrogen stream is used to sweep methanol vapor away fromthe solid addition funnel to prevent caking. Caked material isoccasionally rinsed into the reaction with additional methanol.! Thetemperature of the reaction rises to and is maintained between 50° and60° C. by the continuous addition of borohydride. Complete solutionoccurs early during the addition, then a slurry forms. After addition iscomplete, the reaction temperature is maintained at 50° C. for 60minutes. After cooling to 35° C., hydrochloric acid (358 ml, 6N, 2 mol)is added carefully (no gas evolution is observed but the character ofthe slurry changes). The slurried reaction is concentrated at reducedpressure by rotary evaporation in a 3 liter pear flask. The residue isthoroughly suspended in methanol (700 mL) and then reconcentrated undervacuum to remove boron as trimethyl borate. This is repeated a total ofthree times. At this point the residue consists of L-mannitol and sodiumchloride.

To the residue in the concentration flask is added acetone (2 liter),dimethoxypropane (120 mL), acetic acid (15 mL) and finally concentratedsulfuric acid (27.7 mL). The suspension is shaken on an orbit shakerovernight. The solution is filtered though a sintered-glass funnel toremove the salt. The filtrate is treated with 86 mL of concentratedammonium hydroxide, refiltered, concentrated by rotary evaporation andredissolved in 900 ml of acetone. The acetone solution is poured slowlyinto 2.7 l of cold, vigorously stirred water. Stirring is continued for1 hr. The resulting white triacetonide is collected by filtration,washed with 450 mL of water and dried under vacuum overnight at roomtemperature to yield 195 g (66%) of white plates. mp 66.5°-68° C. (a!20D=-12.6° c=1, ethanol).

The triacetonide of D-mannitol has reported values of (lit.2 m.p.70°-71°, a!20 D=+14.70° (c=1, ethanol); lit.6 m.p. 69°-70°, a!20D=+12.5°(c=9.6, ethanol) ! 2. Kuszmann, J.; Tomori, E. Carb. Res. 1985,137, 276-281. 6. Wiggins, L. J. Chem. Soc. 1946, 13-14.

Part 2: 3, 4-isopropylidene-L-mannitol

Partial deblocking by the method of L.F. Wiggins, J. Chem. Soc., 1946,13-14 gives the tetraol: 3, 4-isopropylidene-L-mannitol.

Part 3: From 3, 4-isopropylidene-L-mannitol

1, 6 ditosyl 2, 5 diacetyl 3, 4 isopropylidene L-mannitol was preparedby the method of L.F. Wiggins, J. Chem. Soc., 1946, 384-388 as describedfor the D-isomer. In general, longer tosylation times (5 days at 0° C. )were preferred. See example 74 for the use of this ditosylate to preparethiepane diol acetonide

Example 2

Table 101, compound 13

L-Mannothiepane diol (Table 101, compound 1)(12.4 g) dried by azeotropicdistillation of toluene, was dissolved in toluene (1700 mL). Toluene(100 mL) was distilled from the reaction. Benzaldehyde (184 mL) wasadded to the refluxing solution followed by aluminum t-butoxide (15.3 g)as a powdered solid. The reaction was continued at reflux for 45 min,cooled, filtered through a celite plug and concentrated. The residue wasthen carefully chromatographed on silica gel with methylene chloridefollowed by 3% ethyl acetate/ methylene chloride to afford thehydroxyenone (Table 101, compound 13)(9.17 g) which was recrystallizedfrom ether/hexane.

mp 132°-133° C.

¹ H NMR 300 MHz (CDCl₃) d 8.053 (s, 1H), 7.87 (m, 2 H), 7.4-7.2 (m, 3H), 5 5.94 (d, J=9.3 Hz, 1H), 4.35 (br q, 1H), 3.84 (dd, J=9.6, 2.4 Hz,1H), 3,15 (dd, J=15.3, 4.5 Hz, 1H), 2.92 (br s, 1H), 2.87 (d, J=15.3 Hz,1H), 1.54 (s, 3H), 1.53 (s, 3H)

¹³ C NMR 75 MHz (CDCl₃) d 194.27, 143.80, 133.81, 131.56, 130.26,129.44, 128.24, 110.30, 80.58, 77.90, 65.28, 37.38, 26.73, 26.25.

UV (methanol) 1=303 nm, e=9000.

Example 3

Table 101, compound 15

Enone (Table 101, compound 13)(5.11 g) and Ni(AcAc)₂ (8.55 g) weredissolved in methylene chloride (350 mL) and ethanol (500 mL) and cooledin an ice bath. Solid sodium borohydride (1.88 g) was added. After 30min, the mixture was concentrated under vacuum and filtered through asilica plug with ethyl acetate to elute the product. Afterconcentration, careful chromatography on silica gel eluting with 3%ethyl acetate/methylene chloride gave diol (Table 101, compound 15)(3.18g) accompanied by other isomers (0.58 g).

¹ H NMR 300 MHz (CDCl₃) d 7.3-7.2 (m, 5 H), 4.76 (dd, J=9.0, 4.0 Hz,1H), 4.31 (ddd, J=9.0, 4.5, 4.0 Hz, 1H), 4.06 (dt, J=4.5, 2.0 Hz, 1H),3.94 (dd, J=9.5, 1.5 Hz, 1H), 3.32 (dd, J=15.0, 8.0 Hz, 1H), 3.0-2.9 (m,3H), 2.72 (br s, 1H), 2.41 (dd, J=15.0, 9.0 Hz, 1H), 2.30 (br s, 1H),1.47 (s, 3H), 1.41 (s, 3H).

¹³ C NMR 75 MHz (CDCl₃) d 138.73, 129.18, 128.71, 126.98, 110.0, 77.10,75.02, 68.23, 66.32, 54.37, 37.82, 35.84, 27.36, 27.03.

UV (methanol) 1=259 nm, e=48; 1=214 nm, e=640.

Example 4

Table 101, compound 25

Diol (Table 101, compound 15)(1.3 g) was dissolved in toluene (250 mL)and dried by azeotropic distillation of 60 mL of toluene. Benzaldehyde(22 mL) was added. An additional 55 ml of toluene was removed bydistillation. Aluminum isopropoxide (2.1 g) was added as a solid. Thereaction was heated to reflux for 7 h, cooled, filtered through a Celiteplug and concentrated. The residue was then carefully chromatographed onsilica with 5% ethyl acetate/methylene chloride to afford the enone(Table 101, compound 25)(0.688 g). along with recovered startingmaterial (0.335 g). A portion of the enone was recrystallized to giveyellow crystals. mp 180°-182° C.

¹ H NMR 300 MHz (CDCl₃) d 8.044 (s, 1H), 7.71 (d, J=7.2 Hz, 2 H),7.3-7.2 (m, 8 H), 5.96 (d, J=9.3 Hz, 1H), 4.23 (br s, 1H), 3.83 (dd,J=9.3, 2.4 Hz, 1H), 3.11 (m, 2H), 2.61 (d, J=3.3 Hz, 2H), 1.59 (s, 3H),1.50 (s, 3H).

¹³ C NMR 75 MHz (CDCl₃) d 194.49, 144.77, 138.07, 133.75, 131.91,130.45, 129.35, 128.65, 128.35, 126.91, 110.26, 80.94, 77.95, 68.27,53.38, 38.77, 26.79, 26.34.

UV (methanol) 1=304 nm, e=22800.

Example 5

Table 101, compounds 26, 28, and 29

Enone (Table 101, compound 25)(1.1 g) with Ni (AcAc)₂ (1.42 g) wasdissolved in methylene chloride (60 mL) and ethanol (110 mL) and cooledin an ice bath. Solid sodium borohydride (315 mg) was added. Thereaction turns dark over 10 min. After 30 min, the mixture wasconcentrated under vacuum and filtered through a silica plug with ethylacetate to elute the product. After concentration, carefulchromatography on silica gel eluting with 2% to 20% ethylacetate/methylene chloride gave the symmetrical diol (Table 101,compound 28)(407 mg), accompanied by other diastereomers (200mg)(including Table 101, compounds 29 and 30).

Symmetrical diol (Table 101, compound 28):

¹ H NMR 300 MHz (CDCl₃) d 7.3-7.15 (m, 10 H), 4.22 (dd, J=4.8, 4.2 Hz,2H), 4.14 (br s, 2H), 3.37 (m, 2H), 3.07 (dd, J=13.8, 9.0 Hz, 2H), 2.78(dd, J=1.38, 6.9 Hz, 2H), 2.44 (d, J=5.4 Hz, 2H), 1.38 (s, 6H).

¹³ C NMR 75 MHz (CDCl₃) d 138.92, 129.14, 128.51, 126.57, 107.81, 76.90,67.64, 46.51, 39.14, 26.78.

Example 6

Table 101, compound 27

To a solution of diol (Table 101, compound 30)(18 mg) in methylenechloride (0.5 mL) was added a solution of Dess-Martin reagent (˜2M inmethylene chloride)(1 mL). Additional reagent was added after 4 and 5hours until the reaction was complete. After completion, the reactionwas quenched with sodium bicarbonate solution and extracted withmethylene chloride. The crude diketone was dissolved in methanol (3 mL).Sodium borohydride (3.8 mg) was added to afford, after workup, thesymmetrical diol (Table 101, compound 28).

The diketone (Table 101, compound 27) was characterized by NMR and useddirectly in the reduction:

¹ H NMR 300 MHz (CDCl₃) d 7.4-7.1 (m, 8H), 6.89 (m, 2H), 4.8 (s, 2H),3.45-3.2 (m, 4H), 2.7 (dd, J=15, 6 Hz, 2H), 1.48 (s, 6H).

¹³ C NMR 75 MHz (CDCl₃) d 199.54, 137.30, 129.61, 128.58, 126.97,112.76,

Example 7

Table 107, compound 1

Diol (Table 101, compound 15)(0.51g) was dissolved in THF (40 mL) andDMSO (20 mL) at 0° C. Sodium hydride (0.48 gm, 60% in oil) was added,followed after 15 min. by benzyl bromide (0.45 mL). After 24 hours, thereaction was quenched with water and extracted into methylene chloride.Chromatography on silica gel with hexane followed by methylene chlorideafforded dibenzyl ether (Table 107, compound 1)(0.81 g) as yellow oil.

¹ H NMR 300 MHz (CDCl₃) d 7.5-7.0 (m, 15 H), 5.094 (d, J=12 Hz, 1H),5.086 (dd, J=8.4, 4.2 Hz, 1H),4.85 (d, J=12.3 Hz, 1H), 4.59 (d, J=12 Hz,2H), 4.23 (dd, J=8.7, 1.5 Hz, 1H), 4.10 (td, J=8.7, 3.9 Hz, 2H), 4.03(t, J=1.5 Hz, 1H), 3.12 (dd, J=15.3, 8.4 Hz, 1H), 2.99 (ddd, J=11.7,6.6, 1.5 Hz, 1H), 2.89 (dd, J=15.3, 6.6 Hz, 1H), 2.79 (dd, J=15.3, 8.4Hz, 1H), 2.46 (dd, J=15.3, 8.4 Hz, 1H), 1.45 (s, 3H), 1.43 (s,3H).

Example 8

Table 107, compound 2

Acetonide (Table 107, compound 1)(0.81 g) was dissolved in methanol (60mL), water (5 mL) and TFA (100 mL) and heated to reflux for 5 h. Thereaction was concentrated under vacuum and chromatographed on silicawith 10% ethyl acetate/methylene chloride to give diol (Table 107,compound 2)(0.36 g) as an oil.

¹ H NMR 300 MHz (CDCl₃) d 7.5-7.0 (m, 15H), 5.00 (d, J=12 Hz, 1H), 4.67(d, J=11.4 Hz, 1H), 4.61 (d, J=12.Hz, 1H), 4.44 (d, J=11.1 Hz, 1H), 4.29(td, J=8.7, 4.5 Hz, 1H), 4.10 (dt, J=9.0, 4.5 Hz, 1H), 4.04 (t, J=1.2Hz, 1H), 3.82 (d, J=9.0 Hz, 1H), 3.22 (br s, 1H), 3.16 (td, J=7.5, 2.4Hz, 1H), 3.14 (dd, J=15,4.5 Hz, 1H), 2.91 (m, 3H), 2.62 (dd, J=15, 5.7Hz, 1H).

Example 9

Table 107, compounds 3, and 4

To a solution of sulfide (Table 107, compound 2)(107 mg) in methanol (12mL) was added a solution of OXONE (73 mg) in water (3 mL). Afterstirring 1 h, the product was extracted into methylene chloride andchromatographed on silica with 2% methanol/methylene chloride to give amixture (85 mg) of sulfoxides as a foam. These were resolved bypreparative reverse phase HPLC to give sulfoxides (Table 107, compound3)(34 mg). and (Table 107, compound 4)(17 mg).

HPLC diastereomer 1 (Table 107, compound 3) 16.958 min; diastereomer 2(Table 107, compound 4) 16.321 min; 20% to 97% methanol/water gradientover 25 minutes, UV 248 nm detection, Rainin Dynamax 3 uM, 4.6 mm×5 cm.C18 column, 1 ml/min flow rate. Diastereomer 1 (Table 107, compound 3):

¹ H NMR 500 MHz (CDCl₃) d 7.5-7.1 (m, 15H), 4.80 (d, J=12 Hz, 1H), 4.71(d, J=12Hz, 1H), 4.69 (d, J=12 Hz, 1H), 4.59 (d, J=11.5 Hz, 1H), 4.51(ddd, J=10, 3, 1.5 Hz, 1H), 4.22 (dd, J=3.5, 1Hz, 1H), 4.10 (dd, J=8,2.5 Hz, 1H), 3.92 (br d, J=6.5 Hz, 1H), 3.54 (br s, 1H), 3.44 (dd,J=14.5, 1Hz, 1H), 3.43 (dd, J=14.5, 7 Hz, 1H), 3.30 (dd, J=14.5, 10 Hz,1H), 3.25 (dd, J=14.5, 7 Hz, lH),3.13 (ddd, J=9, 7.5, 3.5 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 129.44, 128.89, 128.75, 128.25, 128.09,127.15, 79.63, 75.79, 75.79, 73.70, 73.54, 72.58, 71.30, 62.97, 33.74.Diastereomer 2 (Table 107, compound 4):

¹ H NMR 500 MHz (CDCl₃) d 7.5-7.1 (m, 13 H), 6.96 (d, J=6.5 Hz, 2H),5.00 (d, J=11Hz, 1H), 4.80 (d, J=12.5 Hz, 1H), 4.61 (d, J=11.5 Hz, 1H),4.52 (d, J=11 Hz, 1H), 4.32 (dt, J=8.5, 2 Hz, 1H), 3.98 (br s, 1H), 3.77(br m, 1H), 3.68 (d, J=8.5 Hz, 1H), 3.56 (dd, J=11.5,3.5 Hz, 1H), 3.51(m, 2H), 3.31 (d, J=15 Hz, 1H), 2.84 (dd, J=13, 12 Hz, 1H), 2.83 (br s,1H), 2.71 (d, J=6 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 77.42, 77.22, 75.56, 74.90, 74.86,72.23, 67.21, 50.61, 35.39.

Example 10

Table 107, compound 5

To a solution of sulfide (Table 107, compound 2)(98 mg) in methanol (11mL) was added a solution of OXONE (176 mg) in water (3 mL). Afterstirring 15 h, the product was extracted into methylene chloride andchromatographed on silica with 5% methanol in methylene chloride to givesulfone (Table 107, compound 5)(94 mg) as a foam.

¹ H NMR 300 MHz (CDCl₃) d 7.5-7.1 (m, 13H), 6.93 (m, 2H), 4.94 (d,J=11.1Hz, 1H), 4.83 (s, 2H), 4.58 (d, J=11.1Hz, 1H), 4.25 (dd, J=8.4,2.7 Hz, 1H 3.91 (s, 1H), 3.80 (dd, J=11.7, 2.7 Hz, 1H), 3.73 (dd,J=14.7, 8.7 Hz, 1H), 3.64 (d, J=8.4 Hz, 1H), 3.50 (m, 3H), 2.95 (dd,J=14.7, 12 Hz, 1H), 2.51 (m, 2H).

Example 11

Table 107, compound 6

Sodium hydride (60% in oil, 0.1 g) was washed 2× with hexane (5 mL) andsuspended in DMSO (6 mL) and THF (6 mL) under argon. After cooling inice, thiepane diol (Table 101, compound 15)(0.144 g) was added as asolution in THF (6 mL). After gas evolution ceased, o-fluorobenzonitrile(0.2 mL) was added. More THF was added to keep the mixture stirrable.After 3.5 h the mixture was cautiously quenched into 5% citric acidsolution. After extraction into methylene chloride, the product waschromatographed on silica gel with methylene chloride to afford diarylether (Table 107, compound 6)(0.2 g) as a foam. m.p. 81-84 ° C.

¹ H NMR 500 MHz (CDCl₃) d 7.6-6.9 (m, 13H), 5.41 (dd, J=9, 4 Hz, 1H),5.19 (ddd, J=8, 8, 3.5 Hz, 1H), 4.94 (br s, lH), 4.50 (dd, J=9, 2 Hz,1H), 3.47 (dd, J=15.5, 9 Hz, 1H), 3.34 (ddd, J=9.5, 6, 1Hz, 1H), 3.12(dd, J=14, 6.5 Hz, 1H), 2.86 (dd, J=14, 10.5 Hz, 1H), 2.855 (dd, J=15.5,7 Hz, 1H) 1.20 (s, 3H), 1.01 (s, 3H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 134.19, 133.72, 133.48, 133.12, 129.3,128.82, 127.15, 121.53, 116.15, 115.08, 77.69, 76.25, 75.67, 74.52,53.77, 38.2, 35.32, 26.96, 26.38.

Example 12

Table 107, compound 7

Acetonide (Table 107, compound 6)(187 mg) was suspended in water (10 mL)and solubilized with methanol (16 mL) and methylene chloride (5 mL). TFA( 26 mL) was added and the reaction heated to gentle reflux untilcomplete by TLC. The solvents were removed by vacuum to afford afterchromatography, diol (Table 107, compound 7)(106 mg).

¹ H NMR 500 MHz (CDCl₃) d 7.591 (d, J=7.5 Hz, 1H), 7.586 (d, J=7.5 Hz,1H), 7.466 (dd, J=9, 7.5 Hz, 1H), 7.463 (dd, J=9, 7.5 Hz, 1H), 7.225 (m,4H), 7.17 (d, J=8.5 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.089 (t, J=7 Hz,1H), 7.04 (m, 2H), 5.24 (ddd, J=8.5, 4, 4 Hz, 1H), 5.01 (br s, 1H), 4.54(dd, J=9,4 Hz, 1H), 4.27 (dd, J=8.5, 1Hz, 1H), 3.62 (ddd, J=9.5, 6.5, 2Hz, 1H), 3.36 (dd, J=15.5,4 Hz, 1H), 3.03 (dd, J=13.5, 6.5 Hz, 1H), 3.02(dd, J=15, 8.5 Hz, 1H), 2.95 (dd, J=14, 8.5 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 134.71, 134.36 (2C), 133.67, 129.39,128.81, 127.07, 122.39, 121.99, 115.85, 114.81, 81.39, 78.91, 73.29,71.47, 49.88, 39.28, 30.46.

Example 13

Table 107, compound 8

Sulfide (Table 107, compound 7)(72 mg) in methanol (8 mL) and water (2mL) was cooled to 0° C. OXONE (46 mg) as a solid was added followed bymethanol (1 mL). After 2 h, the solvent was removed under vacuum and themixture extracted between methylene chloride and water. The product wasa mixture of sulfoxides. The unpurified mixture showed by HPLC, adiastereomeric ratio of 93:7. After chromatography on silica gel themajor sulfoxide (54 mg), believed to have the stereochemistry indicated(Table 107, compound 8), was characterized as a solid. m.p. 183°-186° C.

¹ H NMR 500 MHz (CDCl₃) d 7.49 (m, 4H), 7.26 (m, 2H), 7.20 (m, 1H), 7.14(m, 4H), 7.03 (t, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 5.31 (d, J=7.5Hz, 1H) 5.00 (br s, 1H), 4.12 (d, J=8.5 Hz, 1H), 3.98 (dd, J=11.5,4 Hz,1H), 3.96 (dd, J=8.5, 2 Hz, 1H), 3.76 (d, J=15 Hz, 1H), 3.64 (dd, J=15,8 Hz, 1H), 3.56 (dd, J=14, 4 Hz, 1H), 2.87 (dd, J=14, 12 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 134.83, 134.43, 133., 129.68, 129.16,127.43, 122.39, 122.22, 114.58, 113.43, 78.21, 75.09, 73.86, 65.73,49.80, 35.55.

HPLC major diastereomer 11.453 min; minor diastereomer 11.916 min, 20%to 97% methanol/water gradient over 25 minutes, UV 292 nm detection,Rainin Dynamax 3 uM, 4.6 mm X 5 cm. C18 column, 1 ml/min flow rate.

Example 14

Table 107, compound 10

Sulfide (Table 107, compound 7)(29 mg) in methanol (3 mL) and water (1mL) was cooled to 0° C. OXONE (50 mg) in water (1 mL) was added followedby methanol (1 mL). After warming to ambient and stirring overnight, themixture was extracted between methylene chloride and water. Afterconcentration the residue was chromatographed on silica gel with 2%methanol in methylene chloride to give sulfone (Table 107, compound10)(27 mg).

¹ H NMR 500 MHz (CDCl₃) d 7.63 (td, J=8.5, 1Hz, 1H), 7.58 (dd, J=8, 1Hz, 1H), 7.55 (dd, J=7.5, 1Hz, 1H), 7.52 (td, J=8.5, 1Hz, 1H), 7.34 (m,2H), 7.32 (d, J=7.5 Hz, 1H), 7.30 (m,2H), 7.19 (d, J=7.5 Hz, 1H), 7.1(m, 1H), 7.08 (m, 1H), 7.07 (d, J=9 Hz, 1H), 5.49 (ddd, J=6.5, 3, 3 Hz,1H), 4.99 (br s, 1H), 4.25 (m, 1H), 4.20 (d, J=8 Hz, 1H), 4.12 (dd,J=11.5,3 Hz, 1H), 3.94 (m, 2H), 3.58 (dd, J=14.5,3 Hz, 1H), 3.32 (d,J=4.5 Hz, 1H), 3.10 (d, J=2 Hz, 1H), 3.01 (dd, J=14.5, 12 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 160.19, 158.10, 135.2, 134.53 (2C),133.59, 129.48, 129.23, 127.64, 122.34, 122.23, 113.54, 112.89, 75.88,75.66, 74.02, 72.07, 67.17, 53.74, 30.17.

Example 15

Table 107, compound 11

By the method of Example 11, compound 15, Table 101, (0.48 g) wasconverted with p-fluorobenzonitrile (0.43 g) into diaryl ether (Table107, compound 11)(0.55 g) after chromatography on silica gel withmethylene chloride.

¹ H NMR 300 MHz (CDCl₃) d 7.54 (d, J=8.7 Hz, 2H), 7.53 (d, J=9 Hz, 2H),7.20 (m, 3 H), 7.05 (d, J=8.7, 2H), 6.98 (d, J=8.7, 2H), 6.90 (m, 2H),5.27 (dd, J=8.7, 3.9 Hz, 1H), 5.08 (td, J=8.1, 3.9 Hz, 1H), 4.87 (s,1H), 4.38 (dd, J=8.4, 1.5 Hz, 1.5 Hz, 1H), 3.45(dd, J=15.6, 8.4 Hz, 1H),3.25 (ddd, J=9.9, 5.7, 1.5 Hz, 1H), 3.04 (dd, J=14.1, 6 Hz, 1H), 2.75(m, 2H). 1.10(s, 3H), 0.95 (s, 3H).

Example 16

Table 107, compound 12

By the method of Example 8, compound 11, Table 107, (550 mg) wasconverted to diol (Table 107, compound 12)(201 mg) after chromatography.

¹ H NMR 300 MHz (CDCl₃) d 7.61 (d, J=9 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H),7.18 (m, 5H), 7.02 (d, J=9, 2H), 6.91 (m, 2H), 5.08 (dd, J=9, 4.8, 3.9Hz, 1H), 4.88 (dd, J=1.8, 1.5 Hz, 1H), 4.58 (dd, J=8.4, 3.9 Hz, 1H),4.14 (dd, J=8.4, 1.5 Hz, 1H), 3.40 (ddd, J=8.7, 6.3, 2.1Hz, 1H), 3.20(dd, J=15.3, 5.4 Hz, 1H), 2.95 (dd, J=13.8, 6 Hz, 1H), 2.83 (dd, J=9,7.5 Hz, 1H), 2.80 (dd, J=9.3, 6 Hz, 1H).

Example 17

Table 107, compounds 13 and 14

By the method of Example 9, compound 12, Table 107, (67 mg) wasconverted to a mixture of sulfoxides. The unpurified mixture showed byHPLC, a diastereomeric ratio of 80:20. After careful chromatography onsilica gel the more polar major diastereomer (14 mg), assigned thestereochemistry indicated (Table 107, compound 13), was obtained. Themixed fractions (50 mg) were separated on reverse phase HPLC to providethe less polar diastereomer (Table 107, compound 14) 2.5 mg for NMRcharacterization.

HPLC major diastereomer 11.856 min; minor diastereomer 12.438 min, 20%to 97% methanol/water gradient over 25 minutes, UV 248 nm detection,Rainin Dynamax 3 uM, 4.6 mm X 5 cm. C18 column, 1 ml/min flow rate.

Major diastereomer (Table 107, compound 13):

¹ H NMR 500 MHz (CDC13/D4-methanol) d 7.54 (d, J=8.5 Hz, 1H), 7.50 (d,J=8.5 Hz, 1H), 7.15 (m, 1H), 7.14 (m, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.90(d, J=7 Hz, 1H), 5.13 (br d, J=8 Hz, 1H), 4.82 (br s, 1H), 3.98 (d, J=8Hz, 1H), 3.93 (d, J=8, 1H), 3.66 (ddd, J=11.5,4, 1.5 Hz, 1H), 3.55 (dd,J=14.5, 8 Hz, 1H), 3.47 (dd, J=14.5, 2 Hz, 1H), 3.42 (dd, J=14.5, 4 Hz,1H), 2.82 (dd, J=13, 12 Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 134.24, 134.13, 129.22, 128.99, 127.35,116.95, 78.49, 74.6, 74.34, 72.79, 67.34, 50.99, 34.39.

UV (methanol) 1=248 nm, e=23500.

Minor diastereomer (Table 107, compound 14):

¹ H NMR 500 MHz (CDC13/D4-methanol) d 7.52 (d, J=7 Hz, 1H), 7.51 (d, J=7Hz, lH), 7.16 (d, J=7Hz, 2H), 7.13 (m, 1H), 7.11 (d, J=9 Hz, 1H), 7.0(d, J=6.5 Hz, 1H), 5.57 (ddd, J=6.5, 4.5, 3 Hz, 1H), 5.0 (br s, 1H),4.14 (dd, J=7, 3 Hz, 1H), 3.98 (dd, J=7, 1H), 3.65 (m, 1H), 3.42 (m,1H), 3.39 (m, 1H), 3.31 (m, 1H), 3.15 (dd, J=16.5, 11Hz, 1H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 134.26, 129.23, 116.56, 80.73, 74.55,72.78, 68.96, 63.07, 45.12, 33.64.

Example 18 Table 107, compound 15

By the method of Example 11, compound 11, Table 107, (79 mg) wasconverted to sulfone (Table 107, compound 15)(66 mg) afterchromatography on silica gel with 2% methanol in methylene chloride.

m.p. 117°-122° C.

¹ H NMR 300 MHz (CDCl₃) d 7.64 (d, J=8.7 Hz, 2H), 7.59 (d, J=8.7 Hz,2H), 7.25 (m, 7 H), 6.85 (m, 2H), 5.36 (dd, J=9.3, 3 Hz, 1H), 4.7 (br s,1H), 4.12 (br d, J=7.5 Hz, 1H), 4.05 (dd, J=7.8, 1.5 Hz, 1H), 3.86 (dd,J=15.3, 9.6 Hz, 1H), 3.65 (ddd, J=10.8, 2.4, 2.1Hz, 1H), 3.52 (d, J=15.6Hz, 1H), 3.51 (dd, J=14.1, 3.9 Hz, 1H), 3.15 (dd, J=9.9, 2.4 Hz, 1H),2.91 (dd, J=14.1, 11.7 Hz, 1H).

Example 19

Table 108, compound 1

Sodium hydride (107 mg, 60% in oil) was added to a THF (5 mL) solutionof diol (Table 101, compound 28)(270 mg). Benzyl bromide (250 uL) wasadded after 10 minutes. DMSO (250 uL) was added and the reaction warmedto 45° C. for 3 h. After extraction between water and methylenechloride, the product was chromatographed on silica gel with 20% ethylacetate/hexane to provide dibenzyl ether (Table 108, compound 1)(360 mg)as an oil.

¹ H NMR 300 MHz (CDCl₃) d 7.4-7.1 (m, 16H), 6.94 (dd, J=7.8, 1.8 Hz,4H), 4.97 (d, J=12 Hz, 2H), 4.55 (d, J=12 Hz, 2H), 4.28 (s, 2H), 4.07(d, J=2.7 Hz, 2H), 3.44 (td, J=7.8, 2.7 Hz, 2H), 2.85 (d, J=7.8 Hz, 4H),1.39 (s, 6H).

UV (methanol) 1=258 nm, e=800

Example 20

Table 108, compounds 1, 2

Sodium hydride (60% in oil, 180 mg) was washed 3× with hexane (5 mL) andsuspended in THF (12 mL) and DMSO (12 mL) under argon. A solution ofdiol (Table 101, compound 28)(364 mg) in THF (13 mL) was added slowly.After gas evolution subsided, the mixture was cooled with an ice bath.Benzyl bromide (0.25 mL) was added via syringe. The reaction was warmedto 40° C. and stirred overnight. After extraction between water andmethylene chloride, the product was chromatographed on silica gel with50% hexane/methylene chloride, 100% methylene chloride and finally 10%ethyl acetate/methylene chloride to afford the dibenzyl ether (Table108, compound 1)(210 mg) as an oil, monobenzyl ether (Table 108,compound 2) (155 mg) and starting diol (62 mg).

Monobenzyl ether (Table 108, compound 2):

¹ H NMR 300 MHz (CDCl₃) d 7.4-7.1 (m, 13 H), 6.98 (dd, J=7.8, 1.8 Hz,2H), 4.89 (d, J=11.7 Hz, 1H), 4.36 (d, J=11.7 Hz, 1H), 4.24 (d, J=9.3Hz, 1H), 4.18 (d, J=4.8 Hz, 1H), 4.07 (dd, J=4.8, 2.7 Hz, 1H), 3.99 (dd,J=9.3, 3 Hz, 1H), 3.69 (dd, J=8.7, 7.5 Hz, 1H), 3.19 (ddd, J=7.8, 7.2,5.1Hz, 1H), 3.08 (dd, J=13.2, 8.4 Hz, 1H), 2.96-2.76 (m, 3H), 2.91 (dd,J=13.8, 7.2 Hz, 1H), 2.85 (dd, J=13.8, 9.3 Hz, 1H) 2.77 (d, J=7.8 Hz,1H), 1.39 (s, 6H).

Example 21

Table 108, compound 3

Acetonide (Table 108, compound 1)(210 mg) was dissolved in methanol (15mL) and methylene chloride (1 mL) with added TFA (22 mL). After heatingto 65° C., the solvent was removed under vacuum. The residue waschromatographed on silica gel with 5% ethyl acetate/methylene chlorideto give 165 mg of diol (Table 108, compound 3) as a white foam.

¹ H NMR 300 MHz (CDCl₃ /D₂ O) d 7.4-7.15 (m, 16H), 7.37 (d, J=6.6 Hz, 4H), 4.76 (s, 4H), 4.06 (br s, 2H), 3.76 (br s, 2H), 3.63 (td, J=7.5, 1.2Hz, 2H), 2.89 (m, 4H).

¹³ C NMR 75 MHz (CDCl₃ /D₂ O) d 139.22, 138.43, 129.11, 128.48, 128.41,127.76, 127.60, 126.46, 80.99, 75.13, 74.37, 46.68, 40.97.

UV (methanol) 1=258.6 nm, e=840.

Example 22

Table 108, compound 4

To a solution of sulfide (Table 108, compound 3)(34.5 mg) in methanol (5mL) was added a solution of OXONE (20 mg) in water (0.5 mL) and stirredfor 1.5 h. After extraction with methylene chloride, the product waschromatographed on silica gel with 10% ethyl acetate/methylene chlorideto provide 30.6 mg of sulfoxide (Table 108, compound 4).

¹ H NMR 300 MHz (CDCl₃ /D₂ O) d 7.5-7.1 (m, 16H), 6.96 (m, 2H ), 5.11(d, J=11.1 Hz, 1H), 4.79 (d, J=11.7 Hz, 1H), 4.71 (d, J=11.1 Hz, 1H),4.64 (d, J=11.7 Hz, 1H), 4.22 (s, 1H), 3.99 (s, 1H), 3.86 (dd, J=12, 3.3Hz, 1H), 3.60 (s, 2H), 3.55 (m, 2H), 3.43 (t, J=7.8 Hz, 1H), 3.09 (dd,J=14.1, 8.4 Hz, 1H), 2.81 (dd, J=16.5, 12 Hz, 1H).

¹³ C NMR 75 MHz (CDCl₃ /D₂ O) d 138.25, 138.04, 137.99, 137.92, 129.30(2C), 128.74, 128.70, 128.47, 128.12, 127.93, 127.85, 126.72, 126.83,82.04, 77.22, 74.68, 74.63, 65.04, 59.41, 36.57, 36.44.

UV (methanol) 1=258.6 nm, e=610.

Example 23

Table 108, compound 5

To a solution of sulfide (Table 108, compound 3)(35.7 mg) in methanol (5mL) was added a solution of OXONE (53 mg) in water (1 mL) and stirredfor 24 hours. After extraction with methylene chloride, the product waschromatographed on silica gel with 8% ethyl acetate/methylene chlorideto provide 32.2 mg of sulfone (Table 108, compound 5) which was thenrecrystallized from hexane.

mp 164-165.

¹ H NMR 300 MHz (CDCl₃ /D₂ O) d 7.5-7.2 (m, 16H), 7.00 (d, J=6 Hz, 4H),5.04 (d, J=11.4 Hz, 2H), 4.79 (d, J=11.4 Hz, 2H), 3.96 (s, 2H), 3.78(dd, J=11.7, 3.0 Hz, 2H), 3.63 (dd, J=11.4,3.0 Hz, 2H), 3.56 (s, 2H),3.03 (dd, J=14.1, 12.0 Hz, 2H).

¹³ C NMR 75 MHz (CDCl₃ /D₂ O) d 137.82, 136.80, 129.40, 128.93, 128.56,128.14, 128.05, 127.05, 76.58, 76.36, 74.95, 66.95, 31.76.

UV (methanol) 1=258.6 nm, e=780.

Example 24

Table 108, compound 6

Sodium hydride (75 mg, 60% in oil) under argon was washed with hexane(2×4 mL). A solution of diol (Table 108, compound 3) in THF (15 mL) wasadded. After gas evolution ceased, a solution of tosyl chloride (75 mg)in THF (30 mL) was added slowly over 75 min. After stirring anadditional 3 h, the reaction was quenched with water and extracted intomethylene chloride. Chromatography on silica with 10% ethylacetate/hexane afforded epoxide (Table 108, compound 6)(131 mg).

¹ H NMR 300 MHz (CDCl₃) d 7.5-7.1 (m, 16H), 7.06 (m, 2H ), 6.84 (m, 2H)4.91 (d, J=12 Hz, 1H), 4.79 (d, J=11.7 Hz, 1H), 4.67 (d, J=12 Hz, 1H),4.53 (d, J=12 Hz, 1H), 4.39 (dd, J=6.3, 1.8 Hz, 1H), 4.01 (d, J=4.2 Hz,1H), 3.29 (m, 2H), 3.16 (dd, J=6.3, 4.5 Hz, 1H), 2.97 (m, 2H), 2.83-2.7(m, 3H)

Example 25

Table 108, compound 7

By the method of Example 22, compound 6, Table 108, (10 mg) wasconverted to sulfoxide (Table 108, compound 7)(4 mg) afterchromatography on silica gel with 5% ethyl acetate in methylenechloride. A single diastereomer was obtained, assigned thestereochemistry depicted.

¹ H NMR 300 MHz (CDCl₃) d 7.4-7.2 (m, 16H), 7.1-7.04 (m, 4H ), 4.77 (brd, J=12 Hz, 1H), 4.71 (d, J=11.7 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 4.59(dd, J=5.7, 1.5 Hz, 1H), 4.37 (d, J=11.7 Hz, 1H), 4.26 (dd, J=4.2,0.9Hz, 1H), 3.83 (br td, J=7.5, 0.9 Hz, 1H), 3.42 (br dd, J=12, 2.7 Hz,1H), 3.243.05 (m, 6H).

Example 26

Table 108, compound 8

Epoxide (Table 108, compound 6)(33 mg) was suspended in acetone (6 ml)and water (3 mL), then treated with sodium bicarbonate (800 mg) andOXONE (60 mg) at RT for 25 min. After quenching with sodium thiosulphate(100 mg) the mixture was reduced under vacuum to 2 mL volume, dilutedwith water (10 mL) and extracted with methylene chloride (3×10 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder vacuum. The residue was triturated with hexane. The solid wascollected by centrifugation and dried under vacuum to provide epoxysulfone (Table 108, compound 8)(31 mg).

¹ H NMR 300 MHz (CDCl₃) d 7.4-7.1 (m, 19H), 6.89 (br s, 1H), 4.89 (d,J=11.7 Hz, 1H), 4.7-4.5 (m, 2H), 4.41 (d, J=12 Hz, 1H), 4.01 (br s, 1H),3.91 (br t, J=6.6 Hz, 1H), 3.57-3.50 (m, 2H), 3.38-3.29 (m, 4H), 3.1-3.0(m, 2H).

Example 27

Table 108, compound 9

By the method of Example 20, compound 28, Table 101, (100 mg) wasalkylated with 3-chloromethylpyridine hydrochloride (300 mg) and NaH(500 mg) to give dipyridyl ether (Table 108, compound 9)(82 mg) afterchromatography on silica with 10% methanol/methylene chloride.

¹ H NMR 300 MHz (CDCl₃) d 8.62 (s, 2H), 8.58 (d, J=4.5 Hz, 2H), 7.71 (d,J=7.5 Hz, 2H), 7.35-7.1 (m, 10H), 6.98 (d, J=6.9 Hz, 2H), 4.97 (d, J=12Hz, 2H), 4.52 (d, J=12 Hz, 2H), 4.28 (s, 2H), 4.1 (d, J=2.7 Hz, 2H),3.41 (td, J=8.1, 2.7 Hz, 2H), 2.86 (d, J=8.1Hz, 4H), 1.37 (s, 6H).

¹³ C NMR 125 MHz HMQC (CDCl₃) d 149.7, 149.5, 149.2, 135.71, 135.57,129.55, 129.41, 129.28, 127.11, 123.86, 79.33, 74.93, 72.39, 72.25,71.94, 65.99, 62.30, 34.87, 32.03, 26.83.

Example 28

Table 108, compound 10

The sulfide (Table 108, compound 9)(70 mg) was dissolved in water (3 ml)and acetone (5 mL) with sodium bicarbonate (800 mg). The solution wascooled to -5° C. and OXONE (90 mg) was added as a solid. After 10 min,the reaction was quenched with sodium thiosulfate (100 mg), diluted withwater (10 mL), then concentrated to half its volume under vacuum andextracted with methylene chloride (3×5 mL). The organic layer was driedover sodium sulfate and concentrated to leave sulfoxide (Table 108,compound 10)(73 mg) which was used directly in the next reaction.

¹ H NMR 300 MHz (CDCl₃) d 8.62 (d, J=4.5 Hz, 1H), 8.61 (d, J=4.5 Hz,1H), 8.58 (s, 1H), 8.55 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.5Hz, 1H), 8H), 7.12 (d, J=6.9 Hz, 2H), 7.01 (d, J=6.9 Hz, 2H), 4.94 (d,J=12.3 Hz, 1H), 4.87 (d, J=12.3 Hz, 1H), 4.66 (d, J=12 Hz, 1H), 4.56 (d,J=12 Hz, 1H), 4.29 (s, 1H), 4.14 (s, 1H), 4.07 (s, 2H), 3.51 (m, 4H),2.91 (m, 2H), 1.35 (s, 6H).

Example 29

Table 108, compound 11

Sulfoxide (Table 108, compound 10)(65 mg) was dissolved in acetone (5mL) and water (3 mL) with sodium bicarbonate (800 mg). At roomtemperature, OXONE (45 mg) was added as a solid. After 30 min, thereaction was quenched with sodium thiosulfate (100 mg), diluted withwater (10 mL), then concentrated to half its volume under vacuum andextracted with methylene chloride (3×5 mL). The organic layer was driedover sodium sulfate and concentrated to afford after chromatography onsilica with 5% methanol/ethyl acetate the sulfone (Table 108, compound11)(18 mg).

¹ H NMR 300 MHz (CDCl₃) d 8.62 (d, J=6.3 Hz, 2H), 8.61 (s, 2H), 7.86 (d,J=7.8 Hz, 2H), 7.38 (dd, J=7.5, 4.8 Hz, 2H), 7.26 (m, 6H), 6.98 ( d,J=7.5 Hz, 4H), 4.97 (d, J=12 Hz, 2H), 4.79 (d, J=12 Hz, 2H), 4.09 (s,2H), 4.01 (s, 2H), 3.60 (dd, J=14.1, 2.4 Hz, 2H), 3.49 (dd, J=11.4, 2.7Hz, 2H), 3.04 (dd, J=13.8, 11.1Hz, 4H), 1.35 (s, 6H).

Example 30

Table 108, compound 14

By the method of Example 21, compound 11, Table 108, (15 mg) wasconverted to diol (Table 108, compound 14)(10 mg) ¹ H NMR 300 MHz(CDCl₃) d 8.50 (s, 2H), 8.45 (d, J=4.5 Hz, 2H), 7.91 (d, J=7.8 Hz, 2H),7.26 (m, 8H), 7.02 (d, J=7.2 Hz, 4H), 5.02 (d, J=11.7 Hz, 2H), 4.87 (d,J=11.7 Hz, 2H), 4.01 (s, 2H), 3.73 (dd, J=11.7, 3 Hz, 2H), 3.70 (m, 4H),3.65 (s, 2H), 3.02 (dd, J=13.8, 12 Hz, 2H).

Example 31

Table 108, compounds 15 and 19

By the method of Example 19, a mixture of diastereomers (330 mg)containing compound 29, Table 101, and compound 30, Table 101, wasbenzylated to the corresponding diethers. After chromatography on silicawith methylene chloride, (Table 108, compound 15)(79 mg) and (Table 108,compound 19)(107 mg) were obtained.

Table 108, compound 15:

¹ H NMR 300 MHz (CDCl₃) d 7.5-6.8 (m, 20H), 4.97 (d, J=11.7 Hz, 1H),4.871 (d, J=12.3 Hz, 1H), 4.867 (dd, J=9,5.7 Hz, 1H), 4.48 (d J=12 Hz,1H), 4.39 (d, J=12 Hz, 1H), 3.98 (br s, 1H), 3.79 (dd, J=9.3, 1.2 Hz,1H), 3.56 (dd, J=5.4, 0.9 Hz, 1H), 2.92 (td, J=7.8, 1.5 Hz, 1H), 2.81(s, 3H), 2.78 (dd, J=14.4, 7.2 Hz, 1H), 2.64 (dd, J=14.1, 7.8 Hz, 1H),1.29 (s, 3H), 1.25 (s, 3H).

Table 108, compound 19:

¹ H NMR 300 MHz (CDCl₃) d 7.4-6.8 (m, 20H), 5.05 (d, J=12 Hz, 1H), 4.88(7, J=8.7 Hz, 1H), 4.60 (d, J=12. Hz, 1H), 4.54 (d, J=11.7 Hz, 1H), 4.36(d J=12 Hz, 1H), 4.07 (br s, 1H), 4.03 (d, J=9 Hz, 1H), 3.56 (dd, J=8.1,3.6 Hz, 1H), 3.11 (m, 3H), 2.76 (m, 3H), 1.42 (s, 3H), 1.37 (s, 3H).

¹³ C NMR 125 MHz HMQC* (CDCl₃) d 84.2, 81.8, 79.3, 76.6, 74.8, 72.4,48.1, 45.5, 40.5, 38.5, 27.2, 27*.

Example 32

Table 108, compound 16

By the method of Example 21, compound 15, Table 108, (58 mg) wasconverted to diol (Table 108, compound 16)(28 mg).

¹ H NMR 300 MHz (CDCl₃) d 7.5-6.9 (m, 20H), 4.98 (d, J=12 Hz, 1H), 4.74(d, J=11.7 Hz, 1H), 4.67 (d J=12 Hz, 1H), 4.66 (d, J=12 Hz, 1H), 4.55(m, 1H), 3.98 (br s, 1H), 3.63 (br s, 1H), 3.61 (br d, J=9.3 Hz, 1H),3.22 (s, 1H), 3.02 (m, 1H), 3.00 (s, 3H), 2.84 (d, J=7.2 Hz, 2H), 2.61(d, J=3.6 Hz, 1H).

¹³ C NMR 75 MHz (CDCl₃) d 139.61, 139.03, 138.58, 129.0, 128.93, 128.50,128.32, 128.23, 127.72, 127.61, 127.52, 127.43, 126.35, 126.22, 85.20,80.99, 74.65, 73.90, 73.24, 72.02, 52.21, 49.26, 38.75, 37.57.

UV (methanol) 1=258.2 nm, e=1100.

Example 33

Table 108, compound 17

By the method of method 22, compound 16, Table 108, (21 mg) wasconverted to a single sulfoxide diastereomer (Table 108, compound 17)(17mg).

¹ H NMR 500 MHz (CDCl₃) d 7.4-7.3 (m, 8H), 7.3-7.2 (m, 8H), 7.01 (d, J=7Hz, 2H), 6.96 (d, J=7 Hz, 1H), 4.99 (d, J=11Hz, 1H), 4.78 (d, J=12Hz,1H), 4.68 (d

Docket No. 216.PC J=11Hz, 1H) 4.64 (d, J=12 Hz, 1H), 4.1-4.0 (m, 3 H),3.51 (m, 2H), 3.45 (ddd, J=10, 5, 2 Hz, 1H), 3.18 (m, 3H), 2.92 (m, 3H).

¹³ C NMR 75 MHz (CDCl₃) d 137.65, 137.08, 129.28, 129.11, 128.83,128.71, 128.60, 128.23, 127.99, 126.95, 126.62, 78.90, 76.75, 76.18,75.28, 72.86, 70.86, 68.34, 68.29, 35.76, 30.34.

UV (methanol) 1=258.4 nm, e=1100.

Example 34

Enzyme Assay

HIV protease assay was performed using the method and materials ofMolecular Probes, Inc., 4849 Pitchford Ave., Eugene, Oreg., 97402-9144,or P.O. BOX 22010, Eugene, Oreg., 97402-0414, (503) 344-3007, FAX (503)344-6504.

Compositions to be subjected to enzyme assay are lyophilited and dilutedin DMSO to 100-1000 μM. Compositions having apparent IC₅₀ <1 μm arediluted to 100 μM.

General

The assay is a fluorometric method for measurement of HIV-protease(HIV-PR) activity utilizing a synthetic peptide substrate for HIV-PRbased on that described by Matayoshi, E.D.; Wang, G.T.; Krafft, G.A.;and Erickson, J.W.; Science, 1990, 247, 954-958; and Wang, G.T.;Huffker, J.A.; Matayoshi, E.; and Krafft, G.A.; Tetrahedron Lett., 1990,165 6493-6496.

Material

Structure: Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Lys(DABCYL)-Arg.

Buffer: 0.1M sodium acetate

1.0M sodium chloride

1.0 mM ethylenediaminetetraacetic acid (EDTA)

1.0 mM dithiothreitol (DTT)

10% dimethyl sulfoxide (DMSO)

1 mg/mL bovine serum albumin (BSA) adjusted to pH 4.7

Enzyme Assay Protocol

1. Prepare a solution of 2 μM HIV Protease Substrate 1 in the AssayBuffer.

2. Dispense the substrate solution into UV-pass fluorescence cuvettes (1cm pathlength).

3. Set the excitation and emission monochromators of thespectrofluorimeter to 340 nm and 490 nm, respectively. To obtain thesame kinetic constants as reported, cuvettes should be held at 37° C.throughout the assay.

4. Begin each assay by adding a small amount (<3% of the final volume)of HIV-PR-containing solution diluted tin the Assay Buffer.

5. Measure the initial rate of cleavage of fluorogenic substrate bymonitoring the increase in fluorescence signal at 490 nm for 5-8 min at37° C.

Example 35

XTT Cell Culture Assay

The method of Weislow, O.S.; Kiser, R.; Fine, D.L.; Bader, J.;Shoemaker, R.H.; and Boyd, M.R.; I. Nat. Cancer Institute, 1989, 81(8)577-586 was applied with the following minor modifications:. Infectionof cells with HIV IIIB was performed without polybrene. Cells weredistributed to Microtiter wells containing the compound of the invention4 h after infection with HIV IIIB. 2×XTT was added at 5-6 days postinfection. 20 μl 2% Triton X-100 was added 1 hour after XTT addition.

XTT Assay Protocol

1. Add 4 ml of XTT (5 mg/ml) to 8 ml of Deficient RPMI medium (no phenolred, no serum). Mix briefly at 45° C. to dissolve XTT.

2. Add 800 μl of PMS (0.2 mg/ml) to XTT/RPMI mixture.

3. Remove 100 4 μl of cell free media from each well of a 96 well plateand replace with 100 μl of the XTT/PMS mixture.

4. Incubate at 37° C. for 1.5-2 h.

5. Read absorbance at 450 nm. Absorbance values are directlyproportional to cell viability.

Cytotoxic Effects Assay Protocol

1. Place 100 4 μl of RPMI+10% FBS into the wells of columns 2-11 of a 96well plate. Do not use outside wells.

2. Make a stock of the compound of the invention that is 10× the desiredhigh concentration to use in a drug dilution series across the plate.

3. Add 25 4 μl of the 10× stock to the appropriate triplicate wells ofcolumn 2 (results in a 1:5 initial stock compound dilution; 2× finalstock compound concentration). Routinely a 500 μM starting stockcompound concentration is used for the cytotoxic effect assay.

4. Mix thoroughly by pipetting, then transfer 25 4 μl across the plateto give 1/5 dilutions through column 10. Column 11 does not get thestock compound.

5. Pipette 2×10⁴ MT2 cells/well (1004 μl) into columns 2-11.

6. Incubate at 37° C. for 5-6 days.

7. Perform XTT assay as described.

Example 36

Activity

The apparent IC₅₀ and IC₅₀ values reported below in Table 25 weredetermined using the assays of Example 34 and 35, respectively. Thevalues are indicated as follows: +=10-50 μM, ++2-10 μM, and +++<2 μM.

Example 37

Table 120 compound 12 and 13

To a solution of 3-pyridylmethylsulfide (Table 120, compound 10)(505 mg)in acetone /water (40 mL; 25:15 containing sodium bicarbonate (800 mg)was added, in 50 mg portions every 10 min., Oxone (500 mg). After theaddition was complete, water (20 mL) was added, and additional portionsof Oxone (400 mg) were added in the same manner. TLC (acetonitrile/water9:1) showed three predominant products (Rf=0.63, 0.48 and 0.27). Themixture was evaporated to a volume of 50 mL. The solution extracted withmethylene chloride (5×20 mL). The extracts were evaporated andchromatographed on silica gel using acetonitrile/water 19:1 to affordsulfone (Table 120, compound 12)(117 mg) corresponding to Rf=0.68. ¹H-NMR (CDCL₃) d 8.63 (m, 2H); 7.87(m, 1H); 7.40-6.95(3m, 5H); 4.97 and4.79 (2d, 2H); 4.01 and 4.09 (2s, 2H); 3.65-3.4 (m, 2H); 3.05 (m, 1H);1.35 (s, 3H).

Further elution with acetonitrile/water 9:1 afforded the mono-N-oxide(Table 120, compound 13)(191 mg) corresponding to the product withRf=0.48. ¹ H-NMR (CDCL₃) d 8.63 (2s, 2H); 8.26 (s, 1H); 8.20 (d, 1H);7.86 (d, 1H); 7.47(d, 1H); 7.38-6.99 (m, 10H); 4.99-4.70 (4d, 4H); 4.11(s, 1H); 4.10 (s, 1H); 4.01 (q, 2H); 3.72-3.50 (m, 5H); 3.16-3.05 (m,3H); 1.35 (s, 6H).

Example 38

Table 120 compound 15

To a solution of 95 mg of sulfone (Table 120, compound 12) in methanol(2 mL) and water (0.2 mL) was added trifluoroacetic acid (3 mL). Themixture was stirred at room temperature for 45 min., then evaporated andcoevaporated with water (2×2 mL). The residue was chromatographed onsilica gel using ethyl acetate/methanol/triethylamine (9:1:1) to affordthe diol (Table 120, compound 15)(77 mg). ¹ H-NMR (CDCL₃) d 8.50-8.53(m, 2H); 7.90 (d, 1H); 7.0-7.37 (m, 5H); 4.86, 5.04 (d, 2H); 4.00 (2,1H); 3.64-3.76 (m, 3H); 3.03 (m, 1H).

UV (methanol) 1 259 e 3190

Example 39

Table 120 compound 16K

Mono-N-oxide sulfone (Table 120, compound 13)(50 mg) was treated by themethod of example 38 to afford diol (Table 120, compound 16)(31 mg) as asolid after chromatography using acetonitrile/water (9:1). ¹ H-NMR(CDCL₃) d 8.55 (s, 1H;); 8.48 (d, 1H); 8.35 (s, 1H); 8.04 (d, 1H); 7.92(d, 1H); 7.52 (d, 1H); 7.0-7.37 (3m, 10H); 4.80-5.01 (m, 4H); 4.02 (s,1H); 3.57-3.83 (m, 7H); 3.05 (m, 2H).

UV (methanol) 1 263 e 15100

Example 40

Table 120 compound 5

The method of example 27 was applied to 400 mg of diol (Table 101,compound 28) using 2-chloromethylpyridine hydrochloride as thealkylating agent to afford the bis ether (Table 120, compound 5)(412 mg)as a crisp foam. ¹ H-NMR (CDCL₃) d 8.55 (d, 1H); 7.76 (m, 1H); 7.73 (m,1H); 7.05-7.28 (m, 6H); 5 5.12 (d, 1H); 4.68 (d, 1H); 4.33 (s, 1H); 4.19(d, 1H); 3.52 (m, 1H); 2.96 (m 2H); 1.33 (s, 3H).

Example 41

Table 120 compound 6 and Table 120 compound 7

The method of example 37 was applied to 400 mg of sulfide (Table 120,compound 5). Chromatography with ethyl acetate afforded sulfone (Table120, compound 6)(186 mg). ¹ H-NMR (CDCL₃) d 8.58 (d, 1H); 7.76-7.83 (m,2H); 7.12-7.33 (m, 6H); 5.17 (d, 1H); 4.78 (d, 1H); 4.20 (s, 1H); 4.11(s, 1H); 3.63 (m, 3H); 3.22 (m, 1H); 1.33 (s, 1H).

Further elution with ethyl acetate/methanol (4:1) afforded themono-N-oxide (Table 120, compound 7). ¹ H-NMR (CDCL₃) d 8.58 (d, 1H);8.25 (d, 1H); 7.12-7.93 (m, 16H); 5.37 (d, 1H); 5.17 (d, 1H); 4.79 (d,2H); 4.22 (d, 2H); 4.06 (m, 2H); 3.67 (m, 4H); 3.19 (m, 2H); 1.34 (s,6H).

Example 42

Table 120 compound 8

The method of example 38 was applied to acetonide (Table 120, compound6)(180 mg) to afford diol (Table 120, compound 8)(107 mg) as a solidafter chromatography using ethyl acetate/methanol (9:1). ¹ H-NMR (CDCL₃)d 8.49 (d, 1H); 7.76 (t, 1H); 7.44 (d, 1H); 7.14-7.26 (m, 6H); 5.16 (d,1H); 4.91 (d, 1H); 4.14 (s, 1H); 3.64-3.80 (m, 3H); 3.15 (t, 1H).

UV (methanol) 1 262 e 7560

Example 43

Table 120 compound 9

The method of example 38 was applied to acetonide (Table 120, compound7)(216 mg) to afford the diol (Table 120, compound 9)(177 mg) as a solidafter chromatography using ethyl acetate/methanol (4:1). ¹ H-NMR (CDCL₃)d 8.49 (d, 1H); 8.26 (d, 1H); 7.85 (d, 1H); 7.77 (t, 1H); 7.44 (t, 1H);7.10-7.26 (m, 14H); 5.27 (m, 2H); 4.87 (m, 2H); 4.18(d, 2H); 3.45-3.80(m, 6H); 3.18 (m, 2H).

UV (methanol) 1 262 e 10300

Example 44

Table 120 compound 17

The method of example 27 was applied to 400 mg of diol (Table 101,compound 28) using 4-chloromethylpyridine hydrochloride as thealkylating agent to afford bis ether (Table 120, compound 17)(142 mg). ¹H-NMR (CDCL₃) d 8.65 (d, 2H); 7.00-7.38 (3m, 7H); 5.00 (d, 1H); 4.50 (d,1H); 4.25 (s,1H);

4.09 (d, 1H); 3.45 (m, 1H); 2.97 (d, 2H); 1.34 (s, 3H)

Example 45

Table 120 compound 18

A solution of sulfide (Table 120, compound 17)(90 mg) in acetone/water(10 mL, 1:1) was added a solution of Oxone (150 mg) in water (2.5 mL).The mixture was stirred for 0.5 h and another portion of Oxone (150 mg)in water (2.5 mL) was added. The mixture was stirred for 0.5 h thensodium thiosulfate (0.5 g) was added. The solution was evaporated to one25 half volume under reduced pressure, and the remaining solution wasextracted with ethyl acetate. The extracts were evaporated to affordsulfone (Table 120, compound 18)(101 mg) as a solid. ¹ H-NMR (CDCL₃) d8.68 (dd, 2H); 7.40 (d, 2H); 7.34 (m, 3H); 7.30 (dd, 2H); 5.03 (d, 1H);4.74 (d, 1H); 4.12 (s, 1H); 4.02 (s, 1H); 3.60 (m, 2H); 3.20 (m, 1H);1.35 (s, 3H).

Example 46

Table 120 compound 19

A suspension of acetonide (Table 120, compound 18)(90 mg) in 1.1 mLmethanol/water (10:1) was treated with 2 mL trifluoroacetic acid. Thesolution was warmed to 600, allowed to stir at room temperature for 15min., then evaporated. The residue was redissolved in 5 mLwater/methanol (2:1), and the pH was adjusted to 8 with solid sodiumbicarbonate. The mixture was evaporated, and the residue was trituratedwith 5 mL water. The ppt was collected by filtration to afford diolsulfone (Table 120, compound 19)(76 mg) as a solid. ¹ H-NMR (CDCL₃) d8.49 (d, 2H); 7.37 (d, 2H); 7.30 (m, 3H); 7.11 (m, 2H); 4.96 (s, 2H);4.04 (s, 1H); 3.76 (m, 2H); 3.12 (m, 1H).

Example 47

Table 120 compound 20

The method of example 27 was applied to 150 mg of diol (Table 101,compound 28) using 2-methyl-4-chloromethylthiazole hydrochloride as thealkylating agent to afford bis ether (Table 120, compound 20)(73 mg). ¹H-NMR (CDCL₃) d 7.05-7.28 (m, 6H); 5.04 (d, 1H); 4.65 (d, 1H); 4.31 (s,1H); 4.15 (d, 1H); 3.44 (m, 1H); 2.83 (d, 2H); 2.89 (s, 3H); 1.35 (s,3H)

Example 48

Table 120 compound 22

The method of example 45 was applied to sulfide (Table 120, compound20)(70 mg) to yield sulfone (Table 120, compound 21)(59 mg) as a foamafter chromatography using methylene chloride/acetone (9:1). A portion(56 mg) of this foam was treated by the method of example 38 to afforddiol (Table 120, compound 22)(44 mg) as a crisp foam afterchromatography using methylene chloride/methanol (19:1). ¹ H-NMR (CDCL₃)d 7.61 (s, 2H); 7.11-7.32 (m, 4H); 5.29 (s, 1H); 5.06 (d, 1H); 4.91 (d,1H); 4.09 (s, 1H); 3.60 (m, 2H); 3.09 (m, 1H); 2.72 (s, 3H). UV(methanol) 1 243 e 5090

Example 49

Table 120 compound 23

The method of example 27 was applied to 620 mg of diol (Table 101,compound 28) using 5-chloromethylthiazole hydrochloride as thealkylating agent to afford bis ether (Table 120, compound 23)(414 mg). ¹H-NMR (CDCL₃) d 8.84 (s, 1H); 7.86 (s, 1H); 7.22 (m, 3H); 6.99 (d, 2H);5.12 (d, 1H); 4.73 (d, 1H); 4.27 (s, 1H); 4.11 (d, 1H); 3.37 (m, 1H);2.82 (d, 2H); 1.41 (s, 3H).

Example 50

Table 120 compound 24

The method of example 45 was applied to sulfide (Table 120, compound23)(160 mg) to afford sulfone (Table 120, compound 24)(38 mg) as an oilafter chromatography using ethyl acetate. ¹ H-NMR (CDCL₃) d 8.89 (s,1H); 7.84 (s, 1H); 7.30 (m, 3H); 6.96 (d, 2H); 5.11 (d, 1H); 5.03 (d,1H); 4.12 (s, 1H); 4.01 (s, 1H); 3.54 (m, 2H); 2.94 (t, 1H); 1.36 (s,3H).

Example 51

Table 120 compound 25

The method of example 38 was applied to sulfone (Table 120, compound24)(36 mg) to afford diol (Table 120, compound 25)(22 mg) as a crispfoam after chromatography using ethyl acetate/methanol (9:1). ¹ H-NMR(CDCL₃) d 8.85 (s, 1H); 7.83 (s, 1H); 7.35 (m, 3H); 6.99 (d, 2H); 5.26(d, 1H); 5.01 (d, 1H); 4.00 (s, 1H); 3.73 (m, 2H); 3.00 (m, 1H).

UV (methanol) 1 240 e 8330 crystals from benzene m.p. 96°-98° C

Example 52

Table 120 compound 31

Sodium Hydride (160 mg, 4 mmol, 60% in oil) was washed 3× with hexane (5mL). Then a solution of diol (Table 101, compound 28)(193 mg, 0.5 mmol)in THF (7 mL) and DMSO (0.25 mL) was added slowly. After 5 minutes,alpha-bromo-m-xylene (202 uL, 1.5 mmol) was added. An additional 4 mmolof NaH was then added. The reaction stirred overnight. After quenchingwith 5% citric acid solution, THF was removed under vacuum and theresidue extracted between water and methylene chloride. Afterconcentration, the organic layer was chromatographed on silica gel with100% methylene chloride to afford the diether sulfide (Table 120,compound 29)(175 mg, 57%)

To a solution of sulfide (Table 120, compound 29 )(175 mg) in acetone(17 mL) and water (6 mL) was added solid sodium bicarbonate (483 mg)followed by OXONE (354 mg). After stirring overnight at ambienttemperature, excess OXONE was quenched with sodium thiosulfate. Afterconcentration under vacuum, the residue was extracted between ethylacetate and water. The organic layer was dried over sodium sulfate andconcentrated to afford sulfone acetonide (181 mg, Table 120, compound30). The crude acetonide was dissolved in methanol (4 mL) and water (0.5mL) followed by trifluoroacetic acid (11 mL). After stirring for 3 hrs,solvents were removed under vacuum and the residue chromatographed onsilica with 2% ethyl acetate in methylene chloride to afford sulfonediol (Table 120, compound 31) (89 mg, 53%) as a white solid mp 157°-159°C.

¹ H NMR 300 MHz (CDCl₃) d 7.32-7.15 (m, 14H), 6.99 (d, J=7.5 Hz, 4H),5.02 (d, J=11.4 Hz, 2H), 4.74 (d, J=11.4, 2H), 3.95 (s, 2H), 3.78 (dd,J=11.7, 2.4 Hz, 2H), 3.49 (dd, J=14.1, 3 Hz, 2H), 3.55 (br s, 2H), 3.01(dd, J=13.5, 12.3 Hz, 2H), 2.38 (s, 6H)

¹³ C NMR 75 MHz (CDCl₃) d 138.39, 137.90, 136.98, 129.59, 129.15,129.09, 128.97, 128.71, 127.22, 125.50, 77.63, 77.00, 76.23, 75.07,67.06, 31.86, 21.61

UV (methanol) Imax 265 e 800

Example 53

Table 120 compound 34

By the method of example 52, diol (Table 101, compound 28)(52.7 mg) wasalkylated with 3-methoxybenzylchloride (40 uL, 3 eq) to afford sulfidediether (Table 120, compound 32)(41.8 mg, 52%). This material wastreated with OXONE (80 mg) in acetone (4 mL) water (1.5 mL) and sodiumbicarbonate (109 mg) for one hour. Excess OXONE was quenched with sodiumthiosulfate. After concentration under vacuum, the residue was extractedbetween ethyl acetate and water. The organic layer was dried over sodiumsulfate and concentrated to afford crude sulfone acetonide (Table 120,compound 33) which was dissolved in methanol (1.5 mL) and water (0.2 mL)followed by trifluoroacetic acid (2.5 mL). After stirring for 1 h,solvents were removed under vacuum and the residue chromatographed onsilica with 5% ethyl acetate in methylene chloride to afford sulfonediol (Table 120, compound 34)(30 mg, 73%) as an oil which recrystallizedfrom methanol as a white solid. mp 153°-154° C.

¹ H NMR 300 MHz (CDCl₃) d 7.32-7.20 (m, 8H), 7.09 (br s, 2H), 7.04-6.95(m, 6H), 6.88 (dd, J=8.1, 1.8 Hz, 2H), 4.98 (d, J=11.7 Hz, 2H), 4.80 (d,J=11.7, 2H), 3.96 (s, 2H), 3.82 (s, 6H), 3.78 (dd, J=11.7, 2.7 Hz, 2H),3.62 (dd, J=14.4, 3 Hz, 2H), 3.59 (s, 2H), 3.03 (dd, J=13.8, 12.3 Hz,2H)

13C NMR (CDCl₃)(75 MHz) 160.28, 139.91, 137.10, 129.92, 129.83, 129.35,127.47, 120.34, 114.27, 113.49, 77.84, 77.42, 77.13, 75.27, 67.36,55.72, 32.12

UV (methanol) Imax 273.8 e 3600

Example 54

Table 120 compound 26

Sodium Hydride (360 mg, 60% in oil) was washed 3× with hexane (10 mL)and suspended in THF (3 mL) and DMSO (0.5 mL). Then a solution of diol(Table 101, compound 28)(204 mg, 0.51 mmol) in THF (2 mL) was addedslowly. After 10 minutes, 2-fluoropyridine (202 mg, 2 mmol) in THF (2mL) was added. The reaction stirred overnight. Upon quenching into water(100 mL) with vigorous stirring, a precipitate formed which wascollected by filtration. The solid was extracted with methylenechloride, dried over magnesium sulfate and concentrated to an oil (147mg). Trituration with methanol gave sulfide diether (Table 120, compound26)(108 mg) as a solid. mp. 193°-199° C.

Example 55

Table 120 compound 27

Sulfide (Table 120, compound 26)(108 mg) in acetone (20 mL) andmethylene chloride (1 mL) was treated with solid sodium bicarbonate (328mg) followed by a solution of Oxone (241 mg) in water (4 mL). When thereaction was complete (TLC) the excess Oxone was quenched with sodiumthiosulfate solution. Acetone was removed under vacuum and the residueextracted between ethyl acetate and water. Trituration of the residuewith methanol gave sulfone acetonide (Table 120, compound 27)(97 mg).

¹ H NMR 500 MHz (CDCl₃) d 8.25 (dm, J=5 Hz, 2H), 7.66 (td, J=10.5, 2 Hz,2H), 7.4-7.35 (m, 8 H), 7.29 (m, 2 H), 6.97 (ddd, J=6.5, 6.0, 1Hz, 2 H),6.91 (d, J=7.5 Hz, 4H), 6.35 (s, 2H), 4.20 (s, 2H), 3.82 (dd, J=11.5, 2Hz, 2H), 3.60 (dd, J=14, 2.5 Hz, 14, 2.5 Hz, 2H), 3.03 (dd, J=14, 11Hz,2H), 1.06 (s, 6H)

HMQC/HMBC8 NMR 125 MHz (CDCl₃) d 163.13, 146.90, 139.46, 137.08, 130.16,129.96, 129.36, 118.45, 111.63, 109.55, 78.50, 72.85, 66.30, 31.46,26.18,

Example 56

Table 120 compound 28

Sulfone acetonide (Table 120, compound 27)(93 mg) was suspended inmethanol (4 mL) and water (1 mL). Complete solution occurred uponaddition of TFA (7 mL). The reaction was heated at 75° for 6 h thenconcentrated to remove reagents and retreated with methanol (2 mL),water (1 mL) and TFA (7 mL) for 4 hrs at 750. After removal of reagentsunder vacuum, the residue was extracted between ethyl acetate and sodiumbicarbonate solution, dried over magnesium sulfate and concentrated togive sulfone diol (Table 120, compound 28)(73 mg)

¹ H NMR 500 MHz (CDCl₃) d 8.17 (dm, J=5 Hz, 2H), 7.75 (td, J=9, 2 Hz,2H), 7.33-7.21 (m, 10 H), 7.06 (m, 4 H), 5.69 (s, 2H), 4.10 (br s, 2H),3.90 (dd, J=11, 3 Hz, 2H), 3.79 (s, 2H), 3.60 (dd, J=14, 3 Hz, 2H), 3.07(dd, J=14, 11.5 Hz, 2H)

**HMQC/HMBC8 NMR 125 MHz (CDCl₃) d 163.13*, 146.54, 140.41, 137.46*,137.08*, 129.8, 129.35, 127.56, 118.91, 112.62, 75.03, 73.88, 68.67,31.48

Example 57

3-benzyloxybenzylbromide

A solution of 3-benzyloxybenzyl alcohol (9.54 g) in methylene chloride(40 ml) with TMSBr (2.5 eq, 13 mL) was heated at reflux for 1 hr. Aftercooling, the reaction was concentrated and then reconcentrated 2 × withmethylene chloride (40 ml). The residue was chromatographed on silicagel eluting first with hexane followed by 10% methylene chloride inhexane to afford 3-benzyloxybenzyl bromide which solidifies on cooling .5.75 g m.p. 38°-40°.

¹ H NMR 500 MHz (CDCl₃) d 7.43-7.3 (m, 5H), 7.22 (t, J=8.1Hz, 1H),7.0-6.9 (m, 2H), 6.88 (ddd, J=8.1, 2.4, 0.6 Hz), 5.021 (s, 2H), 4.417(s, 2H)

Example 58

Table 120 compound 38

Sodium Hydride (120 mg, 60% in oil) was added to a solution of diol(Table 101, compound 28)(200 mg, 0.5 mmol) in THF (4 mL) and DMSO (1mL). After gas evolution stopped, 3-benzyloxybenzyl bromide (414 mg) inTHF (2 mL) was added. The reaction was stirred for 72 h, then quenchedwith 5% citric acid and extracted with methylene chloride.Chromatography on silica gel with 50% hexane/methylene chloride followedby 100% methylene chloride afforded (Table 120, compound 38)(252 mg) asan oil.

¹ H NMR 500 MHz (CDCl₃) d 7.44 (d, J=7.5 Hz, 4H), 7.36 (dd, J=8, 6.5 Hz,4H), 7.33-7.25 (m, 4H), 7.2-7.1 (m, 6H), 7.04 (br s, 2H), 6.97 (d, J=7.5Hz, 2H), 6.96-6.90 (m, 4H), 5.09 (s, 4H), 4.93 (d, J=11.5 Hz, 2H), 4.49(d, J=12 Hz, 2H), 4.26 (s, 2H), 4.04 (d, J=3 Hz, 2H), 3.43 (td, J=8, 2.5Hz, 2H), 2.83 (d, J=7.5 Hz, 2H), 1.37 (s, 6H)

HMQC/HMBC8 (500 MHz) 159.34, 140.92, 139.70, 137.29, 129.67, 129.36,128.81, 128.57, 128.18, 127.71, 126.61, 120.40, 114.42, 114.18, 109.0,79.40, 75.41, 74.08, 70.10, 47.49, 41.03, 26.96

Example 59

Table 120 compound 39

To a solution of sulfide (Table 120, compound 38)(252 mg) in acetone (25mL) was added sodium bicarbonate (534 mg) followed by a solution ofOxone (391 mg) in water (9 mL). After stirring overnight, sodiumthiosulfate (80 mg) was added. Acetone was removed under vacuum. Theresidue was extracted between ethyl acetate and water, dried overmagnesium sulfate and concentrated to give sulfone acetonide (Table 120,compound 39)(269 mg).

¹ H NMR 500 MHz (CDCl₃) d 7.42 (d, J=7.5 Hz, 4 H), 7.34-7.22 (m, 8 H),7.15 (m, 8 H), 6.99 (d, J=7.0 Hz, 2 H), 6.95 (dd, J=8, 2 Hz, 2H), 6.84(m 4H), 5.09 (s, 2H), 4.91 (d, J=13 Hz, 2H), 4.70 (d, J=12.5 Hz, 2H),4.06 (s, 2 H), 4.01 (s, 2H), 3.51 (dd, J=14, 2.5 Hz, 2H), 3.47 (dd,J=11.5, 2.5 Hz, 2H), 2.98 (dd, J=14, 11.5 Hz, 2H), 1.31 (s, 6H)

HMQC/HMBC8 NMR 125 MHz (CDCl₃) d 1159.32, 139.47, 137.2, 137.08, 129.98,129.89, 129.17, 128.81, 128.27, 127.73, 127.28, 120.52, 115.11, 114.21,108.50, 79.97, 74.05, 71.58, 70.87, 70.25, 31.72, 26.83

Example 60

Table 120 compound 40

Acetonide (Table 120, compound 39)(269 mg) was dissolved in a minimumamount of methylene chloride (1 mL) then diluted in methanol (10 mL) andwater (1.3 mL) followed by TFA (13 mL). A portion was chromatographed onsilica gel (3% ethyl acetate in methylene chloride) to afford diolsulfone (Table 120, compound 40)(47 mg) as an oil. UV (methanol) Imax273.8 e 3600

¹ H NMR 300 MHz (CDCl₃) d 7.45-6.9 (m, 28 H), 5.10 (s, 4H) 4.99 (d,J=11.7 Hz, 2H), 4.78 (d, J=11.7 Hz, 2H), 3.95 (s, 2H), 3.78 (dd,J=12,3.3 Hz, 3.63 (dd, J=14.1, 3 Hz, 2H), 3.55 (s, 2 H), 3.03 (dd,J=14.1, 11.7 Hz, 2H)

Example 61

Table 120 compound 41

Diol sulfone ((Table 120, compound 40)(37 mg) in THF (3 mL) was dilutedwith methanol (10 mL) and hydrochloric acid (1 N, 1 mL). Catalyst (10%Pd/C, 20 mg) was added. The reaction flask was evacuated and filled 3×with hydrogen gas at balloon pressure and then stirred for 1 h. Afterfiltering through celite, the mixture was chromatographed on silica geleluting with 5% methanol in methylene chloride to afford the bis phenol(Table 120, compound 41)(26.8 mg) as an oil.

UV (methanol) Imax 276.8 e 2600

¹ H NMR 500 MHz (CDCl₃) d 7.3-7.2 (m, 10 H), 6.97 (d, J=7.5 Hz, 2 H),6.82 (dd, J=8.5, 2 Hz, 2H), 4.92 (d, J=11Hz, 2H), 4.82 (d, J=11Hz, 2H),3.97 (s, 2H), 3.59 (s, 2 H), 3.80 (dd, J=12, 3 Hz, 2H), 3.42 (dd, J=14,2 Hz, 2H), 2.91 (dd, J=13.5, 11.5 Hz, 2H)

HMQC/HMBC8 NMR 125 MHz (CDCl₃) d 157.51, 139.93, 137.09, 129.39, 129.50,128.99, 127.05, 119.70, 115.51, 114.80, 76.62, 76.40, 74.24, 67.30,31.60

Example 62

Table 120 compound 42

Sodium hydride (1.16 g, 60% in oil) was added to a solution of diol(Table 101, compound 28)(1.Olg) in THF (20 mL) and DMSO (5 mL). After 30min, a solution of m-nitrobenzyl bromide (1.626 g ) in THF (5 mL) wasadded and allowed to stir for 60 h. The reaction was carefully quenchedinto 5% citric acid, concentrated to remove THF and extracted withmethylene chloride. Chromatography on silica with methylene chloridegave diether (Table 120, compound 42)(1.18 g ) as a foam.

¹ H NMR 300 MHz (CDCl₃) d 8.26 (s, 2H), 8.19 (d, J=8.1Hz, 2H), 7.70 (d,J=7.5 Hz, 2H), 7.56 (t, J=7.8 Hz, 2H), 7.29-7.20 (m, 6H), 7.03 (d, J=6.6Hz, 4H), 5.05 (d, J=12.6 Hz, 2H), 4.57 (d, J=12.9, 2H), 4.30 (s, 2H),4.13 (d, J=3 Hz, 2H), 3.49 (ddd, J=9.6, 7.2, 3 Hz, 2H), 3.01-2.85 (m,4H), 1.35 (s, 6H)

Example 63

Table 120 compounds 44 and 45

By the method of example 59, sulfide (Table 120, compound 42)(1.18g) wasoxidized with Oxone (2.16 g) to afford sulfone (Table 120, compound 43)(1.2g) which was directly treated with TFA/water/methanol to afford,after chromatography on silica gel with 5% ethyl acetate/methylenechloride, sulfone diol (Table 120, compound 45)(0.795 g) as a solid. mp213-213.4°. ¹ H NMR 500 MHz (CDCl₃) d 8.313 (s, 2H), 8.21 (d, J=8.5 Hz,2H), 7.88 (d, J=7 Hz, 2H), 7.61 (t, J=8 Hz, 2H), 7.31-7.22 (m, 6H), 7.09(d, J=7 Hz, 4H), 5.07 (d, J=12.5 Hz, 2H), 5.01 (d, J=12.5, 2H), 4.01 (s,2H), 3.79 (dd, J=12, 3 Hz, 2H), 3.67 (dd, J=14.5,3 Hz, 2H), 3.65 (s,2H), 3.04 (dd, J=14.5, 12 Hz, 2H), 2.62 (s, 2H)

HMQC (CDCl₃) 133.71, 129.76, 129.51, 129.27, 127.48, 122.91,122.59,77.85, 76.11, 74.12, 67.41, 32.12

UV (methanol) lambda 262.6 epsilon 15400

Further elution with 1% methanol, 10% ethyl acetate/methylene chloride,gave the corresponding sulfoxide (Table 120, compound 44)(0.11 g)

¹ H NMR 500 MHz (CDCl₃) d 8.30 (s, 1H), 8.18 (d, J=7.5 Hz, 1H), 8.15 (d,J=9 Hz, 1H), 8.06 (s, 1H), 7.86 (d, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 1H),7.50 (t, J=7 Hz, 2H), 7.32-7.20 (m, 6H), 7.19 (d, J=7.5 Hz, 2H), 7.06(d, J=7.5 Hz, 2H), 5.23 (d, J=11 Hz, 1H), 4.94 (d, J=12, 1H), 4.84 (d,J=12.5 Hz, 1H), 4.66 (d, J=12.5 Hz, 1H), 4.29 (s, 1H), 4.07 (s, 1H),3.85 (dd, J=11.5, 3.5 Hz, 1H), 3.74-3.67 (m, 2H), 3.63 (dd, J=14.5, 7Hz, 1H), 3.62 (dd, J=13, 3 Hz, 1H), 3.41 (dd, J=8.5, 7.5 Hz, 1H), 3.15(dd, J=14, 8 Hz, 1H), 2.93 (dd, J=13, 12 Hz, 1H), 2.86 (d, J=2.5 Hz,1H), 2.73 (d, J=5 Hz, 1H)

HMQC/HMBC (CDCl₃) 148.39, 140.60, 137.63, 134.09, 133.41, 129.77,129.45, 129.42. 129.27, 127.50, 127.41, 123.05, 122.64, 122.50, 83.5,78.83, 77.25, 74.02, 73.90, 65.27, 59.56, 37.06, 36.83

Example 64

Table 120 compound 46

Sulfone (Table 120, compound 45)(0.795 g) in THF (9 mL), methanol (73mL) and 1N HCl (4.5 mL) with 10% Pd/C (110 mg) was stirred under H2 atatmospheric pressure for 6 h with periodic replacement of the H2atmosphere. After filtration through celite, the solvents were removedunder vacuum and the residue extracted between NaHCO₃ solution and ethylacetate to afford bis aniline sulfone (Table 120, compound 46)(0.692 g)as a foam.

Example 65

Table 120 compound 47

To the free base (Table 120, compound 46) in ethyl acetate (15 mL) wasadded slowly with swirling a solution of methanesulfonic acid (0.22g, 2eq) in ethyl acetate (10 mL). The thick precipitate was broken up withmore ethyl acetate and then collected by filtration. The hygroscopicsolid was dissolved in deionized water and lyophilized to afford the bismethanesulfonate salt tetrahydrate (Table 120, compound 47) as a fluffysolid (0.7685)

¹ H NMR 500 MHz (DMSO) d 7.52 (t, J=7.5 Hz, 2H), 7.44 (d, J=8 Hz, 2H),7.35-7.2 (m, 12H), 7.11 (d, J=7.5 Hz, 2H). 4.93 (d, J=12.3 Hz, 2H), 4.88(d, J=12.2, 2H), 3.67 (dd, J=11.2, 3.4 Hz, 2H), 3.39 (dd, J=13.6, 2.9Hz, 2H), 2.99 (dd, J=13.7, 11.8 Hz, 2H), 2.35 (s, 6H)

Example 66

Table 120 compound 35

By the method of example 62, diol (Table 101, compound 28)(0.206 g) wasalkylated with 3-bromobenzyl bromide (0.38g) to afford afterchromatography on silica gel eluting with 50% hexane/methylene chloridethe sulfide ((Table 120, compound 35)(0.262 g) as an oil.

¹ H NMR 500 MHz (CDCl₃) d 7.546 (s, 2H), 7.45 (br d, J=8 Hz, 2 H),7.32-7.17 (m, 10 H), 6.98 (br d, J=7.0 Hz, 4 H), 4.92 (d, J=13 Hz, 2H),4.48 (d, J=12 Hz, 2H), 4.24 (s, 2 H), 4.05 (d, J=3 Hz, 2H), 3.45 (ddd,J=9.5, 7, 2.5 Hz, 2H), 2.87 (m, 4H), 1.36 (s, 6H)

HMQC NMR 125 MHz (CDCl₃) d 130.82, 130.66, 129.25, 128.73, 126.73,126.19, 79.10, 75.64, 73.38, 47.16, 40.78, 27.03

Example 67

Table 120 compound 36

Oxidation of sulfide (Table 120, compound 35)(0.262 g) with Oxone (0.435g) by the method of example 59 gave sulfone (Table 120, compound 36)(0.25 g) as a foam.

¹ H NMR 500 MHz (CDCl₃) d 7.573 (s, 2H), 7.51 (br d, J=7.5 Hz, 2 H),7.42 (br d, J=7.5 Hz, 2 H), 7.32-7.20 (m, 8 H), 6.95 (br d, J=7.0 Hz, 4H), 4.91 (d, J=12.5 Hz, 2H), 4.76 (d, J=11.7 Hz, 2H), 4.08 (s, 2 H),4.01 (s, 2H), 3.59 (dd, J=13.5, 2.5 Hz, 2H), 3.51 (dd, J=11.5, 3 Hz,2H), 1.35 (s, 6H)

HMQC/HMBC8 NMR 125 MHz (CDCl₃) d 140.15, 136.83, 131.27, 130.95, 130.45,129.75, 129.20, 127.42, 126.60, 108.58, 79.76, 73.39, 71.22, 71.03,31.73, 26.83,

Example 68

Table 120 compound 37

Deprotection of sulfone (Table 120, compound 36)(44.6 mg) in methanol (2mL), water (0.2 mL) with TFA (3 mL) gave a solid which crystallized fromthe reaction mixture. Recrystallization from methanol afforded sulfonediol (Table 120, compound 37)(27.2 mg) m.p. 204°-206° C. UV (methanol) ¹_(max) 259.5 e 835

¹ H NMR 300 MHz (CDCl₃) d 7.601 (s, 2H), 7.48 (br d, J=7.8 Hz, 2 H),7.38 (br d, J=7.5 Hz, 2 H), 7.33-7.20 (m, 8 H), 7.06 (br d, J=6.6 Hz, 4H), 5.05 (d, J=11.7 Hz, 2H), 4.76 (d, J=11.7 Hz, 2H), 3.96 (s, 2 H),3.76 (dd, J=11.7, 3 Hz, 2H), 3.66 (dd, J=14.1, 3 Hz, 2H), 3.58 (s, 2H),3.01 (dd, J=13.8, 11.7 Hz, 2H), 2.45 (br s, 2H)

Example 69

Table 108 compound 16

By the methods of examples 7, and 8 using the diol (Table 101, compound29), the sulfide diol (Table 108, compound 16) was prepared.

Example 70

Table 108 compound 17

Oxidation of sulfide diol (Table 108, compound 16) by the method ofexample 9 gave sulfoxide (Table 108 compound 17) after chromatography.

Example 71

Table 108 compound 18

Oxidation of sulfide diol (Table 108, compound 16) by the method ofexample 9 gave sulphone (Table 108 compound 18).

Example 72

Table 108 compound 21

By the methods of examples 7, 37 and 38 using the diol (Table 101,compound 30), the sulphone diol (Table 108, compound 21) was prepared.

Example 73

Table 108 compound 27

Starting from D-mannitol, by the methods of examples 1, 2, 3, 4, 5, 7,37 and 38, the sulphone diol, (Table 108, compound 27 ) was prepared. Itwas identical by m.p., TLC, NMR and UV to (Table 108, compound 5).

Example 74

(Part 1)

Sodium sulfide (292 g) was dissolved in H₂ O (250 mL) in a 2-neck 2 lround bottom flask with magnetic stirring. To this solution, ethanol(250 mL) was added and heated to reflux. 1,6 ditosyl 2,5 diacetyl 3,4isopropylidene L-mannitol (example 1)(250 g) dissolved in THF was addedslowly to the sodium sulfide solution using an addition funnel over 1 to2 hours. After checking the reaction by tlc (ethyl acetate: methylenechloride=1:4, or methanol: methylene chloride=1:99), the reactionmixture was concentrated. The residue was taken up in 10% ethyl acetatein methylene chloride, then filtered through celite (about 1 cm) using a600 mL sintered glass filter, and concentrated by rotary evaporation.This procedure was repeated twice to remove the white solid completely.The residue was dissolved in methylene chloride (50 - 100 mL) andchromatographed on silica gel.

Flash column chromatography (0.24 mol scale)

    ______________________________________                                        silica gel; 2 l loaded with CH.sub.2 Cl.sub.2                                 fractions;  500 ml each                                                       solvent;    5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                            10% EtOAc in CH.sub.2 Cl.sub.2, 4 l                                                             F1-F8                                                       15% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                             F9-F12                                                      20% EtOAc in CH.sub.2 Cl.sub.2, 6 l                                                             F13-23                                          ______________________________________                                    

Thiepane diol (Table 101, compound 1) eluted as fractions 8-23, 31 g(59% yield).

Example 74

(Part 2)

Diol (Table 101, compound 1)(20 g) was dissolved in toluene (2 l) in a2-neck or 3-neck 3 l round bottom flask with mechanical stirring and adistillation head, and heated to distill off toluene (about 50 to 100mL)*¹. To this hot solution was added benzaldehyde followed immediatelyby finely ground Al(tBuO)3 *². The reaction mixture was stirred for 7min (with toluene distilling from the reaction), then cooled in an icebath. The reaction mixture was filtered through celite (about 1 cm)using a 600 mL sintered glass filter, and washed with methylene chloride(200 mL). The filtrate was concentrated by rotary evaporation. The crudemixture was dissolved in methylene chloride and chromatographed onsilica gel.

Flash column chromatography *3 (130 mmol scale)

    ______________________________________                                        silica gel; 2 l (dry volume)                                                  fractions;  500 ml each                                                       solvent;    CH.sub.2 Cl.sub.2, 6 l                                                                          F1-3                                                        5% EtOAc in CH.sub.2 Cl.sub.2, 8 l                                                              F4-18                                                       20% EtOAc in CH.sub.2 Cl.sub.2, 6 l                                                             F19-29                                          ______________________________________                                    

Enone (Table 101, compound 13) contaminated with benzyl alcohol, elutedas fractions F9-F14 (14.2 g; including benzyl alcohol). Pure enone(Table 101, compound 13) eluted as fractions F15-F20. Afterconcentration, the residue was recrystallized with hexane to obtain awhite solid. This solid (5.84 g) and the impure fractions F9-F14 wereused without further purification for the next step.

Example 74

(Part 3)

To a solution of nickel acetyl acetonate (38.6 g) in methylene chloride(200 mL) in a 3-neck 3 l round bottom flask with thermometer andmechanical stirring, was added enone (Table 101, compound 13)(23 g)dissolved in methylene chloride (100 mL). The remainder of the methylenechloride (700 mL) and ethanol*¹ (1 l) were added to the reactionmixture, then cooled to 0° C. Sodium borohydride as a solid was added tothe reaction mixture in small aliquots*² while maintaining thetemperature at 0° C. After the addition was complete, the reactionmixture was stirred for 15 min to 1 hr at 0° C. More sodium borohydridewas added, if necessary, as indicated by TLC (ethyl acetate :methylenechloride=1:9). The reaction was quenched with 5% citric acid solution(500 mL) and celite (about 50 g). The reaction mixture was stirred for10 min., then allowed to stand for 1 hr. The reaction mixture wasfiltered through celite (about 5 cm in a 2 l sintered glass filterfunnel) to remove the black solids, and washed with water, ethylacetate, and methylene chloride (500 mL each). The organic layers werewashed with 5% citric acid solution, then water. The combined aqueouslayers were back extracted with methylene chloride. The combined organiclayers were dried over sodium sulfate and concentrated by rotaryevaporation. The brown residue was used directly in the next step.

Example 74

(Part 4)

Diol (Table 101, compound 14)(crude mixture) was dissolved in toluene (2l) in a 2-neck or 3-neck 3 l round bottom flask with mechanicalstirring, and heated to distill off toluene. (about 50 to 100 mL)*₁. Tothis hot solution was added benzaldehyde followed immediately by finelyground Al(tBuO)3 *₂. The reaction mixture was stirred for 7 min (withtoluene distilling from the reaction), then cooled in an ice bath. Thereaction mixture was filtered through celite (using 1 inch of celite ina 600 mL sintered glass filter), and the filtrate was concentrated. Thecrude mixture was dissolved in methylene chloride and chromatographed onsilica gel.

Flash column chromatography *3

    ______________________________________                                        silica gel;                                                                             2 l, loaded with 50% hexane CH.sub.2 Cl.sub.2                       fractions;                                                                              500 ml each                                                         solvent;  CH.sub.2 Cl.sub.2, 6 l                                                                              F1-12                                                   3% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                  F13-16                                                  5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                  F17-19                                                  7.5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F20-23                                                  10% EtOAc in CH.sub.2 Cl.sub.2, 4 l                                                                 F24-30                                        ______________________________________                                    

Enone (Table 101, compound 25) eluted in fractions F17-F26. Afterconcentration of these combined fractions, the residue (6.77 g.) wasrecrystallized with hexane to obtain a white solid.

Example 74

(Part 5)

To nickel acetyl acetonate (27 g) dissolved in methylene chloride(100-200 ml) in a 3-neck round bottom flask with thermometer andmechanical stirring, is added enone (Table 101, compound 25)(21 g)dissolved in methylene chloride (100 mL). The remainder of the methylenechloride (700 mL) and ethanol*₁ (1 L) are added to the reaction mixture,then cooled to 0° C. Sodium borohydride is added to the reaction mixturein small aliquots*² while maintaining the temperature at 0° C. After theaddition is complete, the reaction mixture is stirred for 15 min to 1 hrat 0° C. More sodium borohydride is added as necessary as indicated byTLC (ethyl acetate:methylene chloride=1:9)*³. The reaction is quenchedwith 5% citric acid solution (500 mL) and celite (20 to 50 g). Thereaction mixture is stirred for 10 min, then allowed to stand for 1 hrbefore being filtered through celite (300 to 400 g) using a 2 l sinteredglass filter to remove the black solids, and washed with water, ethylacetate and methylene chloride (500 mL each). The organic layers arewashed with 5% citric acid solution, then water. The combined aqueouslayers are back extracted with methylene chloride. The combined organiclayers are dried over sodium sulfate and concentrated. The residue is amixture of diol diastereomers separable by silica gel chromatography.

Flash column chromatography (for about 0.06 mol, 20 g scale)

    ______________________________________                                        silica gel;                                                                             2 l, loaded CH.sub.2 Cl.sub.2                                       fractions;                                                                              500 ml each                                                         solvent;  2.0% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                          2.5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F1-2                                                    3.0% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F3-6                                                    3.5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F7-9                                                    4.0% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F10-13                                                  4.5% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F14-16                                                  6.0% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                F17-20                                                  10% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                 F21-24                                                  15% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                 F25-28                                                  20% EtOAc in CH.sub.2 Cl.sub.2, 2 l                                                                 F29-31                                                  20% EtOAc 2% MeOH in CH.sub.2 Cl.sub.2, 2 l                                                         F32-35                                                  20% EtOAc 4% MeOH in CH.sub.2 Cl.sub.2, 2 l                                                         F36-                                          ______________________________________                                    

A: Diol (Table 101, compound 28) Rf 0.6 Fractions 12-20, ˜40% B/C:ketoalcohols Rf 0.73 (Table 101, compound 31) and (Table 101, compound32)

D: unidentified Rf 0.52, fractions 26-28

E: Diol (Table 101, compound 30) Rf 0.44, fractions 30-33, ˜21%

F: Diol (Table 101, compound 29) Rf 0.31, fractions 35-37

G: unidentified Rf 0.13, fractions 40

Example 75

To a solution of diol (Table 101, compound 30)(0.2 g) in THF (10mL)/DMSO (5 mL) is added sodium hydride (0.2g, 60% in oil). After gasevolution subsides, a solution of m-nitrobenzylbromide (0.108 g) in THF(2 mL0 is added. After 30 min, a solution of citric acid (5 mL, 5% inwater) is added. After extraction with methylene chloride, the productis chromatographed on silica with methylene chloride followed by 5%ethyl acetate / methylene chloride. The monoalkylation product (121mg)(Scheme 8, structure 40 R=m-nitrobenzyl) Rf=0.39 (5% ethylacetate/methylene chloride) was obtained .

Part 2: The monoalcohol (Scheme 8, structure 40 R=m-nitrobenzyl)(121 mg)in acetone (15 ml) was treated with sodium bicarbonate (0.39 g) and asolution of Oxone (0.29 g) in water (2 mL). After 2 hr, a solution ofsodium thiosulfate (0.1 g in 1 mL water) was added. After concentrationto remove acetone, the residue was extracted into methylene chloride toafford sulfone alcohol (Scheme 8, structure 41 R=m-nitrobenzyl)(97 mg)as a white solid.

Part 3: To a solution of sulfone (Scheme 8, structure 41R=m-nitrobenzyl)(94 mg) in methylene chloride (3 ml) /triethylamine (0.3mL) was added a solution of methanesulfonyl chloride (38 uL) inmethylene chloride (1 mL). A second portion was added after 30 min. Thereaction was concentrated to remove volatiles and extracted betweenmethylene chloride and water to afford the vinyl sulfone (Scheme 8,structure 42 R=m-nitrobenzyl)(90 mg) as an oil. Rf 0.68 (5% ethylacetate/methylene chloride).

Part 4: To a solution of vinyl sulfone (Scheme 8, structure 42R=m-nitrobenzyl) (89 mg) in ethanol (2 mL) was added benzyl amine (90mg). The mixture was concentrated under vacuum and redissolved inethanol (2 mL). After stirring for 72 h, an additional portion of benzylamine (90 mg) was added and stirred for an additional 24 hrs. Themixture was concentrated under vacuum and chromatographed on silica gelwith hexane followed by 20% ethyl acetate in hexane to provide the amine(Scheme 17, structure 205 R=m-nitrobenzyl) as an oil (69.6 mg).

¹ H-NMR (CDCL₃) d 8.4-7.0 (19 H), 5.18 (d, J=12.8 Hz, 1H), 4.979 (t,J=8.8 Hz 1H), 4.54 (d, J=12.9 Hz), 4.24 (dd, J=9.1, 1.1Hz), 1H), 4.01(dd, J=2.9, 1.1Hz, 1H), 3.76 (dd, J=13.9, 3.3 Hz, 1H), 3.68 (m, 2H),3.53 (d, J=13.9 Hz, 1H), 3.42 (dt, J=11.7, 3.3, 3.3, 1H), 3.25 (dd,J=13.9, 10.2 Hz, 1H), 3.10 (d, J=8.4 Hz, 1H), 2.75 (dd, J=13.6, 12.4 Hz,1H).

Part 5: The acetonide (Table 108 compound 30)(69.6 mg) in 95% TFA/water(10 mL) was heated to 85° C. Additional water (1 mL) was then added.Heating was continued for 2 hr then water (2 mL) was added. Aftercooling, the mixture was concentrated under vacuum to remove solventsand evaportated twice from methanol. The residue was dissolved inmethylene chloride and treated with 1N NaOH. The organic layer was driedover magnesium sulfate, filtered and concentrated to afford the diol(Table 108 compound 31)(45 mg) as an oil.

¹ H-NMR (CDCl₃) d 8.4-7.0 (19 H), 5.15 (d, J=12 Hz, 1H), 4.78 (d, J=12.5Hz), 4.012 (ddd, J=ll, 5.5,3 Hz, 1H), 3.992 (br s, 1H), 3.90 (d, J=13.5Hz, 1H), 3.83 (t, J=9 Hz, 1H), 3.806 (dd, J=14.5, 3.1Hz, 1H), 3.64 (dd,J=14, 3.5 Hz, 1H), 3.621 (d, J=8.5 Hz, 1H), 3.48 (d, J=13.5 Hz, 1H),3.47 (m, 1H), 3.13 (dd, J=14, 8.5 Hz, 1H), 3.056 (dd, J=15, 11Hz, 1H),3.023 (dd, J=9,5.5 Hz, 1H).

¹³ C-NMR (CDCl₃) d 78.04, 76.64, 74.33,73.56, 66.96, 65.37, 58.90,52.90, 31.65, 31.04.

Example 76

Table 108 compounds 32, 33, 34

To a solution of diol (Table 101 compound 30)(0.2 g) in THF (10 mL) andDMSO (1 mL) was added sodium hydride (0.2 g, 60% in oil). After 10 min,benzyl bromide (86 mg) was added. After 30 min, a solution of citricacid (5 mL, 5% in water) was added. After concentration to remove THF,the residue was extracted into methylene chloride. The crude product waschromatographed on silica gel with methylene chloride followed by 6%ethyl acetate in methylene chlorideto afford the desired monoalkylationproduct (64 mg)(Table 108 compound 32).

Part 2: The monoalcohol (Table 108 compound 32)(64 mg) in acetone (8 mL)was treated with sodium bicarbonate (0.19 g) and a solution of Oxone(0.15 g) in water (1 mL) overnight. Sodium thiosulfate (0.15 g) in waterwas added. After concentration to remove acetone , the residue wasextracted into methylene chloride to afford sulfone alcohol (Table 108compound 33)(63 mg).

Part 3: To a solution of the sulfone alcohol (Table 108 compound 33)(63mg) in methylene chloride (2 mL) and triethylamine (0.2 mL) was added asolution of methanesulfonyl chloride (28 uL) in methylene chloride (0.5mL). After 5 min, a second portion of methanesulfonyl chloride wasadded. After concentration to remove excess triethylamine, the residuewas extracted between methylene chloride and sodium bicarbonatesolution. Chromatography on silica gel with methylene chloride affordedthe vinyl sulfone (Scheme 8, structure 42 R=benzyl)(54 mg) as an oil.

Part 4: Vinyl sulfone (Scheme 8, structure 42 R=benzyl)(54 mg) inmethanol (2 mL) was diluted with water (1 mL) to form a cloudysuspension. Trifluoroacetic acid (TFA)(3 mL) was added. After gentleheating complete solution occured. Additional TFA (2×1 mL) was added andheating continued until starting material was not visible by TLC. Afterconcentration, the residue was reevaporated from methanol and maintainedunder vacuum overnight to afford sulfone diol (Scheme 18, structure 207R=benzyl)(53 mg).

Part 5: Benzyl amine (93 mg) was added to a solution of sulfone diol(Scheme 18, structure 207 R=benzyl)(12.6 mg) in THF (2 ml). This mixturewas concentrated to remove THF and redissolved in ethanol (3 mL). Thesolution was heated to reflux for 24 hr, then continued at ambienttemperature for 72 hr. After concentration the mixture waschromatographed on silica gel with methylene chloride followed by 3%ethyl acetate in methylene chloride to afford the amino diol (Table 108compound 34)(10.3 mg) as an oil.

¹ H-NMR (CDCl₃) d 7.6-6.9 (20 H), 5.03 (d, J=11.5 Hz, 1H), 4.771 (d,J=12 Hz) 4.186 (ddd, J=11, 6, 3 Hz, 1H), 3.969 (s, 1H), 3.968 (d, J=13.5Hz, 1H), 3.803 (m, 1H), 3.667 (m, 1H), 3.601 (d, J=13 Hz, 1H), 3.56 (dd,J=14,3 Hz, 1H), 3.509 (d, J=8.5 Hz, 1H, 3.43 (ddd, J₃₂ 11, 3.5, 1 Hz,1H), 3.09 (m, 1H), 3.08 (m, 1H), 3.07 (m, 1H). ¹³ C-NMR (CDCl₃) d129.53, 129.23, 129.14, 128.66, 128.36, 127.7, 79.56, 75.87, 75.13,74.28, 67.09, 66.25, 58.94, 53.62, 31.70, 30.43.

Example 77

Table 108 compound 35

By the method of Example 76 part 5, sulfone diol (Scheme 18, structure207 R=benzyl)(11.1 mg) was treated with 3-phenyl, 1-aminopropane (50 uL)for 36 h at reflux. After chromatography the amino diol (Table 108compound 35) (8.7 mg) was obtained as a solid. ¹ H-NMR (CD30D) d 7.6-7.0(20 H), 4.955 (d, J=ll Hz, 1H), 4.671 (d, J=11.5 Hz), 3.963 (ddd, J=8.5,5, 3.5 Hz, 1H), 3.896 (br s, 1H), 3.75 (dd, J=9, 8.5 Hz, 1H), 3.724(ddd, J=11.5,4, 1.5 Hz, 1H), 3.642 (dd, J=8, 1Hz, 1H), 3.415 (dd,J=14.5, 4.5 Hz, 1H), 3.398 (dd, J=14, 3.5 Hz, 1H), 3.257 (dd, J=14.5, 8Hz, 1H), 3.019 (dd, J=14, 11.5 Hz, 1H), 2.991 (dd, J=9, 6.5 Hz, 1H),2.607 (ddd, J=11.5, 7.5, 6.5 Hz, 1H), 2.53 (dd, J=8, 7.5 Hz, 2H), 2.392(ddd, J=ll, 9, 7.5 Hz, 1H), 1.630 (p, J=7Hz, 2H). ¹³ C-NMR (CD30D) d142.15, 139.48, 138.5, 137.09, 129.32, 128.72, 128.5, 128.17, 128.12,127.72, 126.81, 125.79, 78.15, 77.66, 75.22, 74.49, 67.16, 65.21, 59.35,48.12, 33.23, 31.77, 31.41, 30.42.

Example 78

Table 101 compounds 40, 43, Table 108 compounds 36, 37, 38

By the method of example 74 part2, thiepane diol (Table 101, compound 1)(0.463 g) was treated with 2-fural to afford after chromatography theenone (Table 101, compound 40) as a solid (0.284 g) mp 139-140 afterrecrystalization from ether.

¹ H-NMR (CDCl₃) d 7.944 (s, 1H), 7.613 (d, J=1.5 Hz, 1H), 7.484 (d J=3.6Hz, 1H), 6.584 (dd, J=3.3, 1.5 Hz, 1H), 5.896 (d, J=9.3 Hz, 1H), 4.444(m, 1H), 3.876 (dd, J=9.3, 2.1Hz, 1H), 3.216 (dd, J=15.3, 4.5 Hz, 1H),2.895 (d, J=15.3 Hz, 1H), 2.704 (br s, 1H). ¹³ C-NMR (CDCl₃) d 145.647,130.804, 119.046, 112.956, 80.532, 77.941, 65.576, 37.163, 26.857,26.405.

Part 2: By the method of example 74 part 3 to 5 but without purificationof intermediates, enone (Table 101, compound 40)(0.28 g) was convertedto the symmetrical diol (Table 101, compound 43)(83.6 mg) as an oilafter chromatography.

¹ H-NMR (CDCl₃) d 7.317 (d, J=1.8 Hz, 2H), 6.288 dd, J=2.7, 1.8 Hz, 2H),6.094 (d J=3.0 Hz, 2H), 4.267 (dd, J=5.4, 3.9 Hz, 2H), 4.224 (s, 2H),3.446 (ddd, J=9, 6.9, 3.9 Hz, 2H), 3.153 (dd, J=15, 9.3 Hz, 2H), 2.916(dd, J=15, 6.6 Hz, 2H), 2.660 (d, J=5.4 Hz, 2H). ¹³ C-NMR (CDCl₃) d152.6, 141.495, 110.31, 107.917, 107.206, 76.529, 68.00, 43.792, 31.834,26.798.

Part 3: By the method of example 62, diol (Table 101 compound 43)(43.6mg) was alkylated with benzyl bromide to afford after chromatography thesulfide (Table 108 compound 36)(56.2 mg) as an oil.

¹ H-NMR (CDCl₃) d 7.374 (m, 10H) 7.263 (d, J=2.1Hz, 2H), 6.220 (dd,J=3.0, 2.1 Hz, 2H), 5.793 (d J=3.0 Hz, 2H), 4.971 (d, J=11.7 Hz, 2H),4.583 (d, J-12 Hz, 2H), 4.367 (s, 2H), 4.135 (d, J=3 Hz, 2H), 3.485(ddd, J=9, 6.3, 3.0 Hz, 2H), 2.953 (dd, J=15, 9.3 Hz, 2H), 2.831 (dd,J=15, 6.3 Hz, 2H).

¹³ C-NMR (CDCl₃) d 153.003, 141.265, 138.616, 128.316, 127.67, 127.523,110.15, 108.124, 106.849, 78.818, 75.533, 74.397, 44.159, 32.918,26.850.

Part 4: The sulfide (Table 108 compound 36)(47 mg) in methanol (3 mL)was treated with a solution of Oxone (51 mg) in water (.4 mL) for 20minutes. Then another portion of Oxone (41 mg) was added. The reactionwas stirred for 4.5 hrs, quenched with sodium thiosulfate solution andextracted between water and methylene chloride. After concentration theresidue was chromatographed on silica gel eluting with methylenechloride to afford the sulfone (Table 108 compound 37)(24.7 mg) as asolid. m.p. 150°-151°.

¹ H-NMR (CDCl₃) d 7.45-7.3 (m, 10H) 7.293 (d, J=1.2 Hz, 2H), 6.215 (dd,J=3.3, 1.2 Hz, 2H), 5.720 (d, J=3.3 Hz, 2H), 4.964 (d, J=12 Hz, 2H),4.780 (d, J=12.3 Hz, 2H), 4.162 (s, 4H), 3.622 (dd, J=11.4, 3.0 Hz, 2H),3.455 (dd, J=15, 3.0 Hz, 2H), 3.195 (dd, J=15.3, 11.7 Hz, 2H).

¹³ C-NMR (CDCl₃) d 150.013, 142.367, 137.649, 128.493, 127.879, 127.824,110.429, 108.859, 108.831, 79.454, 74.437, 71.415, 68.453, 26.669,24.659.

Part 5: Sulfone (Table 108 compound 37)(17.5 mg) suspended in methanol(2 mL) and water (0.5 mL). TFA (2 mL) added. As the mixture warms, thesuspension dissolves. After 30 minutes, the solvents were removed undervacuum. The residue was reevaporated from methanol to afford the sulfonediol (Table 108 compound 38)(17 mg).

¹ H-NMR (CDCl₃) d 7.5-7.3 (m, 10H) 7.348 (d, J=1.5 Hz, 2H), 6.297 (dd,J=2.5, 1.5 Hz, 2H), 5.948 (d, J=3 Hz, 2H), 5.035 (d, J=11.5 Hz, 2H),4.796 (d, J=11.5 Hz, 2H), 4.064 (s, 2H), 3.898 (dd, J=12,3.5 Hz, 2H),3.743 (s, 2H), 3.553 (dd, J=15.5, 3.5 Hz, 2H), 3.226 (dd, J=15.5, 11.5Hz, 2H), 2.757 (br s, 2H).

Example 79

Table 125 compound 36

Sodium hydride (200 mg, 5 mmol, 60% in oil) was washed 3× with hexane (5mL). Then a solution of diol (Table 101, compound 28)(250 mg, 0.62 mmol)in THF (8 mL) and DMSO (0.3 mL) was added slowly. After 10 min, 4bromo-2 methyl-2-butene (216 uL, 1.67 mmol) was added via syringe. After1 hr, 5% cirtic acid solution was added, THF was removed under vacuumand the residue extracted between water and methylene chloride. Afterconcentration the organic layer was chromatographed on silica geleluting with methanol to afford the diether sulfide (Table 125, compound36)(238 mg) as an oil.

¹ H-NMR (CDCl₃) d 7.4-7.0 (m, 10H), 5.383 (br t, J=6.9 Hz, 2H), 4.358(dd, J=11.7, 6.6 Hz, 2H), 4.173 (s, 2H), 4.056 (dd, J=11.4, 7.2 Hz, 2H),3.949 (d, J=2.7 Hz, 2H), 3.379 (ddd, J=9.0, 6.3, 2.7 Hz, 2H), 2.950 (dd,J=13.8, 9.3 Hz, 2H), 2.855 (dd, J=13.8, 6.3 Hz, 2H), 1.755 (s, 6H),1.642 (s, 6H), 1.378 (s, 6H).

¹³ C-NMR (CDCl₃) d 139.201, 135.55, 129.05, 128.164, 126.128, 121.7,107.553, 78.889, 74.524, 68.946, 46.727, 40.056, 26.617, 25.682, 18.016.

Example 80

Table 125 compound 19

A solution of the diol (Table 101, compound 28)(100 mg) in THF (2 mL)and t-Butanol (0.5 mL) was treated with potassium t-butoxide (200 mg)and 2- fluro-5-methylpyridine (0.4 mL). The mixture was stirred at 55°for 17 h. The mixture was partitioned between water and ethyl acetate,the organic layer was washed with brine, dried over sodium sulfate andevaporated. The residue was triturated with methanol and the precipitatewas collected by filtration to afford 69 mg of solid.

Example 81

Table 125 compound 20

A solution of compound 19 (Table 125)(60 mg) in acetone (15 mL) andwater (5 mL) was treated with sodium bicarbonate (200 mg) and oxone (100mg). The mixture was stirred for 30 min and a solution of oxone (100 mg)in water (5 mL) was added. The mixure was stirred for an additional 30min and sodium thiosulfate was added (200 mg). The mixture was dilutedwith water and extracted with methylene chloride. The organic extractswere washed with water, dried over magnesium sulfate and evaporated toafford 58 mg of foam.

Example 82

Table 125 compound 21

A solution of compound 20 (Table 125)(40 mg) in trifluoroacetic acid (5mL) and water (0.1 mL) was stirred for 24 h and then evaporated. Theresidue was crystallized from benzene/hexane (1 mL, 1:1) to afford 18 mgof solid. ¹ H-NMR:(CDCl₃) d: 8.03 (s, 1H); 7.68 (dd, 1H); 7.4-7.0(3m,6H); 5.31 (s, 1H); 3.99 (dd, 1H); 3.85 (s, 1H); 3.62 (dd, 1H); 3.07(dd, 1H); 2.35 (s,3H).

Example 83

Table 125 compound 25

The method of example 80 was applied to the diol (Table 101, compound28)(100 mg) using 4-nitro-3-trifluoromethylfluorobenzene (0.4 mL) as thearylating agent to obtain 66 mg of a glass after chromatography onsilica gel using ethyl acetate/hexane/methylene chloride 1:1:6.

Example 84

Table 125 compound 26

The method of example 81 was applied to compound 25 (Table 125)(60 mg)to obtain 50 mg of crude material after chromatography on silica gelusing ethyl acetate/hexane/methylene chloride 1:1:6.

Example 85

Table 125 compound 27

A solution of compound 26 (Table 125)(45 mg) in trifluoroacetic acid (5mL) and water (0.1 mL) was warmed to 750 and then stirred for 1 h at rt.The mixture was then evaporated. The residue was triturated with etherto afford 8 mg of solid. ¹ H-NMR:(CDCl₃) d: 8.02 (d, 1H); 7.61 (d, 1H);7.4-6.9 (3m,6H); 4.84 (s, 1H); 3.92 (s, 1H); 3.90 (dd, 1H); 3.67 (dd,1H); 2.88 (dd, 1H).

Example 86

Table 125 compound 28

A solution of compound 27 (Table 125)(100 mg) in ethanol (5 mL) wastreated with a drop of glacial acetic acid and hydrogenated over Raneynickel (0.25 cc) under a hydrogen balloon for 1 h. The catalyst wasremoved by filtration, the filtrates were evaporated and the residuechromatographed on silica gel using ethyl acetate to afford 88 mg of acrisp foam. ¹ H-NMR:(CDCl₃) d: 7.4-6.8 (8m,6H); 4.49 (s, 1H); 4.1(bs,2h); 3.8 (dd, H); 3.76 (s, 1H); 3.6 (dd, 1h); 2.93 (dd, 1H); 2.53(bs, 1H).

Example 87 Table 125 compound 15

The method of example 80 was applied to the diol (Table 101, compound28)(50 mg) using 4-nitrofluorobenzene (0.2 mL) as the arylating agent toobtain 34 mg of a crisp foam after chromatography on silica gel usingethyl acetate/hexane/methylene chloride 1:1:6.

Example 88

Table 125 compound 16

The methods of example 81 and 82 were applied to compound 15 (Table125)(30 mg) to obtain 21 mg of material after crystallization fromether. ¹ H-NMR:(CDCl₃) d: 8.28 (dd, 1H); 7.4-6.9 (8m,8H); 4.87 (s, 1H);3.95 (s, 1H); 3.91 (dd, 1H); 3.66 (dd, 1h); 2.89 (dd, 1H).

Example 89

4-(chloromethyl)-2-bromothiazole

A suspension of 4-(chloromethyl)-2-aminothiazole hydrochloride (4.0 g)in aqueous hydrobromic acid (48%, 50 mL) was chilled in an ice-salt bathand a solution of sodium nitrite (2.0 g) in water (20 mL) was added withstirring over a 10 min period. The mixture was stirred for 1 h, then theice bath was removed and the mixture was stirred for an additional 3 h.The pH was adjusted to 5 with solid sodium bicarbonate and extractedwith methylene chloride. The organic extracts were evaporated and theresidue was chromatographed on silica gel using methylenechloride/hexane 1:1. The elution was followed by TLC using the samesolvent system and fractions containing the product with Rf=0.4 wereevaporated to yield 320 mg of the product. ¹ H-NMR:(CDCl₃) d: 8.78(s,1H); 4.70 (s,2H).

Example 90

Table 125 compound 11

To a solution of the diol (Table 101, compound 28) in THF (2 mL) andDMSO (0.2 mL) was added 60% sodium hydride oil dispersion (50 mg). Afterstirring for 5 min, 4-(chloromethyl)-2-bromothiazole (200 mg) was added.The mixture was stirred at 550 for 6 h. The mixture was partionedbetween ethyl acetate and water, the organic layer was evaporated andthe residue chromatographed on silica gel using ethylacetate/cyclohexane 1:2 to afford 150 mg of an oil.

Example 91

Table 125 compound 12

In a solution of dimethylamine in THF (2M) was dissolved compound 11(Table 125)(50 mg) and the mixture was heated at 2000 at 175 psi in asteel bomb for 3 h. The mixture was evaporated and the residuechromatographed on silica gel using ethyl acetate/hexane 1:1. Thefractions containing the product with Rf=0.25 were evaporated to yield23 mg of product.

Example 92

Table 125 compound 13

To a solution of compound 12 (Table 125) in acetone (10 mL) and water (7mL) was added, with stirring three portions of oxone (150 mg each) every30 min. The mixture was stirred an additional 30 min after the lastaddition and sodium thiosulfate was added (100 mg). The mixture wasevaporated and the residue was partiotioned between methylene chlorideand water. the organic layer was dried over sodium sulfate andevaporated to afford 18 mg of product.

Example 93

Table 125 compound 14

A solution of compound 13 (Table 125) in trifluoroacetic acid (1.5 mL),methanol (0.5 mL) and water (0.1 mL) was heated at 500 for 30 min. Themixture was evaporated, the residue was treated with two drops ofconcentrated ammonium hydroxide and evaporated. This residue waschromatographed on silica gel using ethyl acetate/methanol 9:1 to afford9.7 mg of material. ¹ H-NMR:(CDCl₃) d: 7.4-7.2 (m,5H); 6.51 (s,1H); 4.94and 4.65 (2d,2H); 4.08 (s,1H); 3.8-3.6 (2dd,2H); 3.57 (s,1H); 3.1(m,7H).

Example 94

Table 125 compound 7

To a solution of the diol (Table 101, compound 28)(300 mg) in THF (3 mL)and DMSO (0.3 mL) was added 60% sodium hydride oil dispersion (150 mg).After stirring for 5 min, 5-(chloromethyl)-2-chlorothiazole (378 mg) wasadded. The mixture was stirred at 550 for 24 h. The mixture waspartioned between ethyl acetate and water, the organic layer wasevaporated and the residue chromatographed on silica gel using ethylacetate/cyclohexane 1:2 to affor 193 mg of an oil.

Example 95

Table 125 compound 8

In a solution of dimethylamine in THF (2M) was dissolved compound 7(Table 125)(50 mg) and the mixture was heated at 135° at 100 psi in asteel bomb for 12 h. The mixture was evaporated and the residuechromatographed on silica gel using ethyl acetate to yield 23 mg ofproduct.

Example 96

Table 125 compound 9

The method of example 92 was applied to compound 8 (Table 125)(30 mg) toafford 19 mg of material.

Example 97

Table 125 compound 10

The method of example 93 was applied to compound 9 (Table 125)(15 mg) toafford 9.2 mg of material. ¹ H-NMR:(CDCl₃) d: 7.25-6.98 (m,6H); 6.51(s,1H); 4.96 and 4.67 (2d,2H); 3.92 (s,1H); 3.7-3.5 (2dd,2H); 3.47 (s,1H); 3.05 9m, 7H).

Example 98

Table 125 compound 18

The method of example 86 was applied to compound 17 (Table 125)(10 mg)to afford 7.5 mg of material. ¹ H-NMR:(CDCl₃) d:7.3-6.7 (m,9H); 4.56 (s,1H); 3.93 (dd, 1H); 3.80 (s, 1H); 3.63 (dd, 1H); 3.05 (dd, 1H).

Example 99

Table 125 compound 37

A solution of compound 36 (Table 125)(45 mg) in ethanol (2 mL) wastreated with 10% palladium on carbon (100 mg) and was stirred under 500psi of hydrogen pressure for 14 h. The catalyst was removed byfiltration and the filtrates were evaporated to yield 42 mg of material.

Example 100

Table 125 compound 37

The method of example 81 was applied to compound 37 (Table 125) (40 mg)to afford 32 mg of material.

Example 101

Table 125 compound 38

The method of example 85 was applied to compound 37 (Table 125)(30 mg)to afford 12.5 mg of material after chromatography on silica gel usingethyl acetate/heaxane 1:5. ¹ H-NMR:(CDCl₃) d: 7.4-7.2 (m,5H); 4.05 (dd,1H); 3.81 (s, 1H); 3.8-3.6 (m,3H); 3.46 (s, 1H); 3.09 (dd, 1H); 1.75(sep, H); 1.48 (m,2H); 0.94 (2d,6H).

Example 102

Table 125 compound 32

A solution of compound 47 (Table 120)(50 mg) in pyridine (2 mL) wastreated with trimethylchlorosilane (0.25 mL). The mixture was stirredfor 1 h and methanesulfonyl chloride (0.1 mL) was added. The mixture wasstirred for 3 hours and concentrated ammonium hydroxide (2 mL) wasadded. The mixture was stirred for 1 h and evaporated. The residue waspartitioned between ethyl acetate and water and the organic layer waswashed with water and brine, evaporated, and the residue waschromatographed on silica gel using ethyl acetate/hexane 1:1 to afford48 mg of material. ¹ H-NMR:(DMSO-d₆) d: 9.80 (s, 1H); 7.4-7.0 (m,8H);4.85 (2d,2H); 3.84 (s, 1H); 3.66 (dd, H); 3.45 (s, 1H); 3.01 (s,3H);2.95 (dd, 1H).

Example 103

Table 125 compound 24

The methods of example 80,81,83 were applied to the diol (Table 101,compound 28)(100 mg) to yield 33 mg of material. ¹ H-NMR:(CDCl₃) d: 7.99(dd, 1H); 7.55 (d, 1H); 7.4-7.2 (3m,5H); 6.95 (dd, 1H); 5.84 (s, 1H);3.94 (dd, 1H); 3.78 (s, 1H); 3.59 (dd, 1H); 3.03 (dd, 1H); 2.42 (s,3H).

Example 104

Table 125 compound 31

The methods of example 80,81,83 were applied to the diol (Table 101,compound 28)(100 mg) to yield 17 mg of material. ¹ H-NMR:(CDCl₃) d: 7.62(dd, 1H); 7.4-7.2 (3m,6H); 6.87 (dd, 1H); 5.62 (s, 1H); 3.88 (dd, 1H);3.76 (s, 1H); 3.58 (dd, 1H); 3.09 (dd, 1H); 2.46 (s,3H).

Example 105

Table 125 compound 35

The methods of example 80,81,83 were applied to the diol (Table 101,compound 28)(100 mg) to yield 21 mg of material. ¹ H-NMR:(CDCl₃) d: 8.04(dd, 1H); 7.4-7.2 (3m,6H); 6.90 (bs, 1H); 5.48 (s, 1H); 3.93 (dd, 1H);3.80 (s, 1H); 3.61 (dd, 1H); 3.07 (dd, 1H); 2.42 (s,3H).

                  TABLE 25                                                        ______________________________________                                        Table/Compound                                                                            Apparent Enzyme IC50                                                                         Cell Culture IC50                                  ______________________________________                                        107/2       +              N/T                                                107/3       ++             N/T                                                107/4       ++             +                                                  107/5       +++            +                                                  107/8       +              N/T                                                107/10      ++             N/T                                                107/12      ++             N/T                                                107/13      +              N/T                                                107/15      ++             N/T                                                108/3       ++             ++                                                 108/4       +++            +++                                                108/5       +++            +++                                                108/17      N/T            ++                                                 108/17      ++             N/T                                                108/18      +++            +                                                  108/21      +++            +++                                                108/27      +              +                                                  108/31      +++            ++                                                 108/34      +++            ++                                                 108/35      +++            ++                                                 120/2       +++            +                                                  120/3       +++            +                                                  102/4       +++            +++                                                120/8       +++            ++                                                 120/9       +++            ++                                                 120/15      +++            +++                                                120/16      +++            +++                                                120/19      +++            N/T                                                120/22      +++            +                                                  120/25      +++            +++                                                120/28      +++            N/T                                                120/31      +++            +++                                                120/34      +++            +++                                                120/37      +++            N/T                                                120/40      +++            N/T                                                120/41      +++            N/T                                                120/44      +++            +++                                                120/45      +++            +++                                                120/46      +++            +++                                                125/14      +++            N/T                                                125/17      +++            +++                                                125/21      ++             N/T                                                125/27      +++            N/T                                                125/28      +++            +++                                                128/31      +              N/T                                                128/35      +              N/T                                                ______________________________________                                    

What is claimed is:
 1. A composition comprising a compound of theformula: ##STR200## wherein: each Y is independently --N(R₁)--,--N(R₁)--SO₂ -- or --N(R₁)--CO--;E and U are independently H, or --(CR₁R₁)_(m1) --W₁, with the proviso that at least one of E and U is --(CR₁R₁)_(m1) --W₁ ; G and T are independently --(CR₁ R₁)_(m1) --W₁, or--(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), with the provisos that: when E is--(CR₁ R₁)_(m1) --W₁, then G is --(CR₁ R₁)_(m1) --W₁ ; when U is --(CR₁R₁)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁ ; and G and T may be thesame or different; J and L are independently H, N₃, --OR₂, --N(R₂)(R₂),or --N(R₂)(R₃), wherein R₂ is H, or PRT, with the proviso that at leastone of J and L is --OR₂, or J and L are taken together to form anepoxide, or a cyclic protecting group; W₁ is W₂ or W₃ ; W₂ iscarbocycle, with the proviso that each W₂ is independently substitutedwith 0 to 3 R₅ groups; W₃ is alkyl, alkenyl, or alkynyl, with theproviso that each W₃ is independently substituted with 0 to 3 R₆ groups;R₁ is R₃ or R₆ ; R₃ is H or R₄ ; R₄ is alkyl; R₅ is R₆, or R₇, with theproviso that each R₇ is independently substituted with 0 to 3 R₆ groups;R₆ is --O--(label), --N(R₃)--(label), --C(O)O--(label),--C(O)N(R₃)--(label), --S--(label), --S--S--(label), F, Cl, Br, I, --CN,N₃, --NO₂, --OR₃, --OPRT, --O--C(O)R₄, ═O, --N(R₃)(R₃), --N(R₃)(PRT),--N(PRT)₂, --N(R₃)--C(O)R₄, ═N(R₃), ═N(PRT), --N(OR₃)(R₃),--N(OPRT)(R₃), --N(OR₃)(PRT), --N(OPRT)(R₃), --N(N(R₃)(R₃))(R₃),--N(N(PRT)(R₃))(R₃), --N(N(R₃)(R₃))(PRT), --N(N(PRT)(PRT))(R₃),--N(N(PRT)(R₃))(PRT), --N(N(PRT)(PRT))(PRT), --N(R₃)--C(N(R₃))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)₂), --N(R₃)--C(N(PRT))(N(R₃)₂),--N(R₃)--C(N(R₃))(N(R₃)(PRT)), --N(PRT)--C(N(PRT))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)(PRT)), --N(R₃)--C(N(PRT))(N(R₃)(PRT)),--N(R₃)--C(N(R₃))(N(PRT)₂), --N(PRT)--C(N(PRT))(N(R₃)(PRT)),--N(PRT)--C(N(R₃))(N(PRT)₂), --N(R₃)--C(N(PRT))(N(PRT)₂),--N(PRT)--C(N(PRT))(N(PRT)₂), --C(NR₃)(N(R₃)₂), --C(N(R₃))(N(R₃)(PRT)),--C(NPRT)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂),--C(N(PRT))(N(PRT)₂), --SR₃, --S(PRT), ═S, --S(O)--R₃, --S(O)--OR₃,--S(O)-OPRT, --O--S(O)--R₃, --S(O)₂ --R₃, --S(O)₂ --OR₃, --S(O)₂ --OPRT,--O--S(O)₂ --R₃, --C(O)OR₃, --C(O)OPRT, --C(O)N(R₃)₂, --C(O)N(R₃)(PRT),--C(O)N(PRT)₂, --C(S)N(R₃)₂, --C(S)N(R₃)(PRT), --C(S)N(PRT)₂,--N(R₃)--S(O)₂ --R₃, --N(PRT)--S(O)₂ --R₃, --S(O)₂ --N(R₃)--R₃, --S(O)₂--N(PRT)--R₃, carbocycle, or heterocycle; R₇ is alkyl, alkenyl; each m1is independently an integer from 0 to 3; and with the proviso that thecompound, taken as a whole, contains 0 to 16 R₆ groups, and that each E,G, T, and U, taken individually, contain 0 to 8 R₆ groups.
 2. Thecomposition of claim 1 wherein each Y is --N(R₁)--.
 3. The compositionof claim 1 wherein G and T independently are --(CR₁ R₁)_(m1) --W₂. 4.The composition of claim 1 wherein G and T independently are --(CR₃R₃)_(m1) --W₂.
 5. The composition of claim 1 wherein E and Uindependently are --(CR₁ R₁)_(m1) --W₂.
 6. The composition of claim 1wherein E and U independently are --(CR₃ R₃)_(m1) --W₂.
 7. Thecomposition of claim 1 wherein E and U independently are --(CR₁ R₁)_(m1)--W₁ ; and T and G independently are --(CR₁ R₁)_(m1) --W₁.
 8. Thecomposition of claim 1 wherein E and U independently are --(CR₃ R₃)_(m1)--W₁ ; and T and G independently are --(CR₃ R₃)_(m1) --W₁.
 9. Thecomposition of claim 1 wherein E and U independently are --(CR₁ R₁)_(m1)--W₂ ; and T and G independently are --(CR₁ R₁)_(m1) --W₂.
 10. Thecomposition of claim 1 wherein E and U independently are --(CR₃ R₃)_(m1)--W₂ ; and T and G independently are --(CR₃ R₃)_(m1) --W₂.
 11. Thecomposition of claim 1 wherein one of E and U is H and the other is--(CR₁ R₁)_(m1) --W₁ ; and T and G independently are --(CR₁ R₁)_(m1)--W₁.
 12. The composition of claim 1 wherein one of E and U is H and theother is --(CR₃ R₃)_(m1) --W₁ ; and T and G independently are --(CR₃R₃)_(m1) --W₁.
 13. The composition of claim 1 wherein one of E and U isH and the other is --(CR₁ R₁)_(m1) --W₂ ; and T and G independently are--(CR₁ R₁)_(m1) --W₂.
 14. The composition of claim 1 wherein one of Eand U is H and the other is --(CR₃ R₃)_(m1) --W₂ ; and T and Gindependently are --(CR₃ R₃)_(m1) --W₂.
 15. The composition of claim 1wherein one of E and U is H and the other is --(CR₁ R₁)_(m1) --W₁ ; andwith the proviso that:when E is H, G is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂),when E is --(CR₁ R₁)_(m1) --W₁, G is --(CR₁ R₁)_(m1) --W₁, when U is H,T is --(CR₁ R₁)_(m1) --C(R₁)W₁)(W₂), and when U is --(CR₁ R₁)_(m1) --W₁,T is --(CR₁ R₁)_(m1) --W₁.
 16. The composition of claim 1 wherein one ofE and U is H and the other is --(CR₃ R₃)_(m1) --W₁ ; and with theproviso that:when E is H, G is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), when Eis --(CR₃ R₃)_(m1) --W₁, G is --(CR₁ R₁)_(m1) --W₁, when U is H, T is--(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), and when U is --(CR₃ R₃)_(m1) --W₁, Tis --(CR₁ R₁)_(m1) --W₁.
 17. The composition of claim 1 wherein one of Eand U is H and the other is --(CR₁ R₁)_(m1) --W₂ ; and with the provisothat:when E is H, G is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), when E is --(CR₁R₁)_(m1) --W₂, G is --(CR₁ R₁)_(m1) --W₁, when U is H, T is --(CR₁R₁)_(m1) --C(R₁)(W₁)(W₂), and when U is --(CR₁ R₁)_(m1) --W₂, T is--(CR₁ R₁)_(m1) --W₁.
 18. The composition of claim 1 wherein one of Eand U is H and the other is --(CR₃ R₃)_(m1) --W₂ ; and with the provisothat:when E is H, G is --(CR₁ R₁)_(m1) --C(R₁)(W₁)(W₂), when E is --(CR₃R₃)_(m1) --W₂, G is --(CR₁ R₁)_(m1) --W₁, when U is H, T is --(CR₁R₁)_(m1) --C(R₁)(W₁)(W₂), and when U is --(CR₃ R₃)_(m1) --W₂, T is--(CR₁ R₁)_(m1) --W₁.
 19. The composition of claim 1 wherein thecompound is of the formula: ##STR201##
 20. The composition of claim 1wherein J and L are --OH.
 21. The composition of claim 1 wherein one ofJ and L is --OH and the other is H.
 22. The composition of claim 1wherein one of J and L is --OH and the other is --NH₂.
 23. Thecomposition of claim 1 wherein J and L are taken together to form##STR202##
 24. A composition comprising a compound of the formula:##STR203## wherein: Y is independently --O--, --S--, --SO--, --SO₂ --,--N(R₁)--, --N(R₁)--SO₂ --, --N(R₁)--CO--, or --O--SO₂ --;E and U areindependently H, or --(CR₁ R₁)_(m1) --W₁, with the proviso that at leastone of E and U is --(CR₁ R₁)_(m1) --W₁ ; G and T are independently--(CR₁ R₁)_(m1) --W₁, or --(CR₁ R₁)_(m1) --C(R₁)W₁)(W₂), with theprovisos that: when E is --(CR₁ R₁)_(m1) --W₁, then G is --(CR₁ R₁)_(m1)--W₁ ; when U is --(CR₁ R₁)_(m1) --W₁, then T is --(CR₁ R₁)_(m1) --W₁ ;and G and T may be the same or different; J and L are independently H,N₃, --OR₂, --N(R₂)(R₂), or --N(R₂)(R₃), wherein R₂ is H, or PRT, withthe proviso that at least one of J and L is --OR₂, or J and L are takentogether to form an epoxide, or a cyclic protecting group; W₁ is W₂ orW₃ ; W₂ is carbocycle, with the proviso that each W₂ is independentlysubstituted with 0 to ₃ R₅ groups; W₃ is alkyl, alkenyl, or alkynyl,with the proviso that each W₃ is independently substituted with 0 to ₃R₆ groups; R₁ is R₃ or R₆ ; R₃ is H or R₄ ; R₄ is alkyl; R₅ is R₆, orR₇, with the proviso that each R₇ is independently substituted with 0 to3 R₆ groups; R₆ is --O--(label), --N(R₃)--(label), --C(O)O--(label),--C(O)N(R₃)--(label), --S--(label), --S--S--(label), F, Cl, Br, I, --CN,N₃, --NO₂, --OR₃, --OPRT, --O--C(O)R₄, ═O, --N(R₃)(R₃), --N(R₃)(PRT),--N(PRT)₂, --N(R₃)--C(O)R₄, ═N(R₃), ═N(PRT), --N(OR₃)(R₃),--N(OPRT)(R₃), --N(OR₃)(PRT), --N(OPRT)(R₃), --N(N(R₃)(R₃))(R₃),--N(N(PRT)(R₃))(R₃), --N(N(R₃)(R₃))(PRT), --N(N(PRT)(PRT))(R₃),--N(N(PRT)(R₃))(PRT), --N(N(PRT)(PRT))(PRT), --N(R₃)--C(N(R₃))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)₂), --N(R₃)--C(N(PRT))(N(R₃)₂),--N(R₃)--C(N(R₃))(N(R₃)(PRT)), --N(PRT)--C(N(PRT))(N(R₃)₂),--N(PRT)--C(N(R₃))(N(R₃)(PRT)), --N(R₃)--C(N(PRT))(N(R₃)(PRT)),--N(R₃)--C(N(R₃))(N(PRT)₂), --N(PRT)--C(N(PRT))(N(R₃)(PRT)),--N(PRT)--C(N(R₃))(N(PRT)₂), --N(R₃)--C(N(PRT))(N(PRT)₂),--N(PRT)--C(N(PRT))(N(PRT)₂), --C(NR₃)(N(R₃)₂), --C(N(R₃))(N(R₃)(PRT)),--C(NPRT)(N(R₃)₂), --C(N(PRT))(N(R₃)(PRT)), --C(N(R₃))(N(PRT)₂),--C(N(PRT))(N(PRT)₂), --SR₃, --S(PRT), ═S, --S(O)--R₃, --S(O)--OR₃,--S(O)--OPRT, --O--S(O)--R₃, --S(O)₂ --R₃, --S(O)₂ --OR₃, --S(O)₂--OPRT, --O--S(O)₂ --R₃, --C(O)OR₃, --C(O)OPRT, --C(O)N(R₃)₂,--C(O)N(R₃)(PRT), --C(O)N(PRT)₂, --C(S)N(R₃)₂, --C(S)N(R₃)(PRT),--C(S)N(PRT)₂, --N(R₃)--S(O)₂ --R₃, --N(PRT)--S(O)₂ --R₃, --S(O)₂--N(R₃)--R₃, --S(O)₂ --N(PRT)--R₃, carbocycle; R₇ is alkyl, alkenyl, oralkynyl; each m1 is independently an integer from 0 to 3; and with theproviso that the compound, taken as a whole, contains 1 to 16 R₆ groups,and that each E, G, T, and U, taken individually, contain 0 to 8 R₆groups, and that one or more R₆ groups is selected from the groupconsisting of --O--(label), --N(R₃)--(label), --C(O)O--(label),--C(O)N(R₃)--(label), --S--(label), --S--S--(label), ═O, ═N(R₃),═N(PRT), --N(OR₃)(R₃), --N(OPRT)(R₃), --N(OR₃)(PRT), --N(OPRT)(R₃),--N(N(R₃)(R₃))(R₃), --N(N(PRT)(R₃))(R₃), --N(N(R₃)(R₃))(PRT),--N(N(PRT)(PRT))(R₃), --N(N(PRT)(R₃))(PRT), --N(N(PRT)(PRT))(PRT), ═S,--S(O)--R₃, --S(O)--OR₃, --S(O)--OPRT, --O--S(O)--R₃, --S(O)₂ --R₃,--S(O)₂ --OR₃, --S(O)₂ --OPRT, --O--S(O)₂ --R₃, --C(S)N(R₃)₂,--C(S)N(R₃)(PRT), --C(S)N(PRT)₂, --N(R₃)--S(O)₂ --R₃, --N(PRT)--S(O)₂--R₃, --S(O)₂ --N(R₃)--R₃, --S(O)₂ --N(PRT)--R₃.
 25. The composition ofclaim 24 wherein one or more R₆ groups is selected from the groupconsisting of --O--(label), --N(R₃)--(label), --C(O)O--(label),--C(O)N(R₃)--(label), --S--(label) and --S--S--(label).
 26. Thecomposition of claim 24 wherein one or more R₆ groups is selected fromthe group consisting of --N(OR₃)(R₃), --N(OPRT)(R₃), --N(OR₃)(PRT),--N(OPRT)(R₃), --N(N(R₃)(R₃))(R₃), --N(N(PRT)(R₃))(R₃),--N(N(R₃)(R₃))(PRT), --N(N(PRT)(PRT))(R₃), --N(N(PRT)(R₃))(PRT) and--N(N(PRT)(PRT))(PRT).
 27. The composition of claim 24 wherein one ormore R₆ groups is selected from the group consisting of --S(O)--R₃,--S(O)--OR₃, --S(O)--OPRT, --O--S(O)--R₃, --S(O)₂ --R₃, --S(O)₂ --OR₃,--S(O)₂ --OPRT and --O--S(O)₂ --R₃.
 28. The composition of claim 24wherein one or more R₆ groups is selected from the group consisting of--C(S)N(R₃)₂, --C(S)N(R₃)(PRT), --C(S)N(PRT)₂, --N(R₃)--S(O)₂ --R₃,--N(PRT)--S(O)₂ --R₃, --S(O)₂ --N(R₃)--R₃ and --S(O)₂ --N(PRT)--R₃. 29.The composition of claim 24 wherein one or more R₆ groups is aheterocycle.